Franz H. Messerli, MD; Giuseppe Mancia, MD; C. Richard Conti, MD; Ann C. Hewkin, MSc; Stuart Kupfer, MD; Annette Champion, MBA; Rainer Kolloch, MD; Athanase Benetos, MD; Carl J. Pepine, MD
ClinicalTrial.gov identifier: NCT00133692.
Note: The first author, Dr. Messerli, has had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Grant Support: By research grants from Abbott.
Potential Financial Conflicts of Interest: Employment: F.H. Messerli (Abbott, Novartis, Pfizer Inc., Sankyo), A.C. Hewkin (Abbott), S. Kupfer (Abbott), A. Champion (Abbott); Consultancies: F.H. Messerli (Abbott, Norvartis, Pfizer Inc., Merck & Co. Inc.), C.J. Pepine (Abbott Laboratories, CV Therapeutics); Honoraria: G. Mancia (Pfizer Inc., Novartis Pharma, Sanofi-Synthelabo, Servier, Abbott, Merck Sharp & Dohme, Bayer, Boehringer Ingelheim), A. Benetos (Abbott, Servier, Bayer); Stock ownership or options (other than mutual funds): A.C. Hewkin (Abbott), S. Kupfer (Abbott), A. Champion (Abbott); Expert testimony: F.H. Messerli (Novartis); Grants received: F.H. Messerli (Novartis), C.J. Pepine (Abbott Laboratories, AstraZeneca, Berlex Laboratories Inc., CV Therapeutics, GlaxoSmithKline, King Pharmaceuticals Inc., Millennium Pharmaceuticals, Inc., Monarch Pharmaceuticals, Pfizer Inc., Sanofi-Aventis, Schering-Plough, Wyeth-Ayerst Laboratories); Grants pending: F.H. Messerli (GlaxoSmithKline); Patents received: C.J. Pepine (University of Florida). Abbott markets 2 of the study drugs (verapamil and trandolapril) and their fixed-dose combination.
Requests for Single Reprints: Franz H. Messerli, MD, Division of Cardiology, St. Luke's-Roosevelt Hospital, 1000 Tenth Avenue, New York, NY 10019; e-mail, Fmesserli@aol.com.
Current Author Addresses: Dr. Messerli: Division of Cardiology, St. Luke's-Roosevelt Hospital, 1000 Tenth Avenue, New York, NY 10019.
Dr. Mancia: Dipartimento di Medicina Clinica, Università degli Studi di Milano–Bicocca, Ospedale San Gerardo di Monza, Via Donizetti 106, 20052 Monza, Milan, Italy.
Drs. Conti and Pepine: Division of Cardiovascular Medicine, 1600 SW Archer Road, Box 100277, Gainesville, FL 32610-0277.
Ms. Hewkin: DR435, AP9A, Abbott, 200 Abbott Park Road, Abbott Park, IL 60045.
Dr. Kupfer: 640 Colwyn Terrace, Deerfield, IL 60015.
Ms. Champion: DR439, AP30-3, Abbott, 200 Abbott Park Road, Abbott Park, IL 60045-6145.
Dr. Kolloch: Gilead Medical Center, University of Munster, Munster, Germany.
Dr. Benetos: Centre de Geriatrie, Hôpital Brabois, University of Nancy, 54511 Nancy-les-Vandoeuvre, France.
Author Contributions: Conception and design: F.H. Messerli, G. Mancia, S. Kupfer, R. Kolloch, C.J. Pepine.
Analysis and interpretation of the data: F.H. Messerli, G. Mancia, C.R. Conti, A.C. Hewkin, S. Kupfer, A. Champion, R. Kolloch, A. Benetos, C.J. Pepine.
Drafting of the article: F.H. Messerli, G. Mancia, A.C. Hewkin, S. Kupfer, R. Kolloch, A. Benetos, C.J. Pepine.
Critical revision of the article for important intellectual content: F.H. Messerli, G. Mancia, C.R. Conti, S. Kupfer, A. Champion, R. Kolloch, A. Benetos, C.J. Pepine.
Final approval of the article: F.H. Messerli, G. Mancia, C.R. Conti, R. Kolloch, A. Benetos, C.J. Pepine.
Provision of study materials or patients: F.H. Messerli, C.R. Conti, C.J. Pepine.
Statistical expertise: F.H. Messerli, A.C. Hewkin.
Obtaining of funding: C.J. Pepine.
Administrative, technical, or logistic support: C.J. Pepine.
Collection and assembly of data: F.H. Messerli, C.J. Pepine.
Messerli F., Mancia G., Conti C., Hewkin A., Kupfer S., Champion A., Kolloch R., Benetos A., Pepine C.; Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?. Ann Intern Med. 2006;144:884-893. doi: 10.7326/0003-4819-144-12-200606200-00005
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Published: Ann Intern Med. 2006;144(12):884-893.
For 2 decades, the hypertension literature has been haunted by the phenomenon of a “paradoxical” increase in morbidity and mortality with an excessive decrease in blood pressure (J-curve). Indeed, several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications (1-13). After doing a review and meta-analysis of pertinent studies, Farnett and colleagues (14) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure, there was a consistent J-shaped relationship for cardiac events and diastolic pressure. These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may “leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease.” These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) (15), which stated that the relationship between pressure and risk was “strong, continuous, independent, predictive and etiologically significant.” Within the past decade, the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients (16-30).
Cardiology Dept, Klinikum Wels, Austria, St VincentÂ´s Clinic, Sydney, Australia
June 27, 2006
Diastolic blood pressure in coronary artery disease
In a recent issue of the Annals, Messerli et al provide new insights into the J-curve discussion in patients with hypertension and coronary artery disease (CAD) . Briefly, they observed an increase in all-cause mortality and myocardial infarctions with lower diastolic blood pressure in the INVEST population, hypertensive patients with CAD, treated with a verapamil sustained release or atenolol-based strategy . In the discussion, the authors mention impaired coronary perfusion, increased pulse pressure and arterial stiffness, and underlying chronic illness as possible pathophysiologic mechanisms.
Clearly, we cannot speculate on the latter, but would like to support the two other explanations due to the following reasons: First, mean patient age in INVEST was 66 years. Generally, in this age group, isolated systolic hypertension (ISH) is by far the most common phenotype of hypertension , a condition characterized by widened pulse pressure, increased arterial stiffness, increased/premature arterial wave reflections, therefore decreased diastolic blood pressure and impaired coronary perfusion [4,5]. In the original publication, more than 50% of patients had "controlled" diastolic blood pressure at baseline, raising the possibility of ISH in many of them. It would be very interesting to perform complementary analysis in ISH patients, if they had been identified at baseline. Second, Chirinos et al  as well as our group  recently observed that increased arterial wave reflections, one of the main pathophysiologic principles contributing to an increased pulse pressure in these patients, are accompanied by an increase in major adverse cardiovascular events including myocardial infarction and death in CAD patients. In the Chirinos paper  as well as in a prior study showing a relationship between increased arterial wave reflections and the presence and extent of CAD , a lower diastolic blood pressure was a predictor of the unfavourable endpoint. Moreover, in the latter study, systolic blood pressure was identical in CAD and non-CAD patients, and the significant difference in pulse pressure was mediated mainly by a lower diastolic blood pressure in the CAD group. In other words, the only clue to the altered arterial characteristics in CAD patients was a lower diastolic pressure. Of note, most of the CAD patients in that study were treated hypertensives with a mean age of 63.8 years and, therefore, quite comparable to the INVEST population.
In conclusion, although arterial properties were not reported in the INVEST study [1,2], the increased risk accompanying a lower diastolic blood pressure in treated hypertensive patients with CAD might be explained by increased arterial wave reflections and arterial stiffness.
Michael F. O`Rourke
1 ... Messerli FH, Mancia G, Conti R, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006; 144:884-93
2 ... Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. J Am Med Ass 2003; 290:2805-16
3 ... Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives - analysis based on NHANES III. Hypertension 2001; 37:869-74
4 ... Nichols WW, OÂ´Rourke MF. McDonaldÂ´s Blood Flow in Arteries. 5th ed. London, England:Hodder-Arnold, 2005
5 ... Franklin SS. Hypertension in older people: Part 1. J Clin Hypertens 2006; 8:444-9
6 ... Chirinos JA, Zambrano JP, Chakko S, et al. Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coronary artery disease. Hypertension 2005;45:980"“985
7 ... Weber T, Auer J, OÂ´Rourke MF, et a. Increased arterial wave reflections predict severe cardiovascular events in patients undergoing percutaneous coronary interventions. Eur Heart J 2005; 26:2657-63
8 ... Weber T, Auer J, OÂ´Rourke MF, et al. Arterial stiffness, wave reflections and the risk of coronary artery disease. Circulation 2004; 109:184-198
Hean T Ong
HT Ong Heart Clinic, Penang, MALAYSIA
July 1, 2006
How to reduce systolic blood pressure without lowering the diastolic ?
Messerli and colleagues suggest that there is a nadir for diastolic blood pressure below which coronary perfusion is impaired and cardiovascular events increased (1). Yet, numerous trials including VALUE and ASCOT clearly show that the arm treated to the lower blood pressure produce less cardiovascular events (2,3). How can we seek to "lower blood pressure" and yet try to "not lower diastolic blood pressure excessively" since all present anti-hypertensive agents lower both diastolic and systolic pressures??
References: 1. Messerli FH, Mancia G, Conti R, et al. Dogma disputed: Can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006; 144:884-893.
2.Julius S,Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet 2004; 363: 2022 -31.
3. Dahlof B,Sever PS,Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366:895-906.
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Cardiology, Nephrology, Hypertension, Coronary Risk Factors, Coronary Heart Disease.
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