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ARTICLE

Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?

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; and Carl J. Pepine, MD

20 June 2006 | Volume 144 Issue 12 | Pages 884-893

Background: Because coronary perfusion occurs mainly during diastole, patients with coronary artery disease (CAD) could be at increased risk for coronary events if diastolic pressure falls below critical levels.

Objective: To determine whether low blood pressure could be associated with excess mortality and morbidity in this population.

Design: A secondary analysis of data from the International Verapamil-Trandolapril Study (INVEST), which was conducted from September 1997 to February 2003.

Setting: 862 sites in 14 countries.

Patients: 22 576 patients with hypertension and CAD.

Interventions: Patients from INVEST were randomly assigned to a verapamil sustained-release– or atenolol-based strategy; blood pressure control and outcomes were equivalent.

Measurements: An unadjusted quadratic proportional hazards model was used to evaluate the relationship between average on-treatment blood pressure and risk for the primary outcome (all-cause death, nonfatal stroke, and nonfatal myocardial infarction [MI]), all-cause death, total MI, and total stroke. A second model adjusted for differences in baseline covariates.

Results: The relationship between blood pressure and the primary outcome, all-cause death, and total MI was J-shaped, particularly for diastolic pressure, with a nadir at 119/84 mm Hg. After adjustment, the J-shaped relationship persisted between diastolic pressure and primary outcome. The MI–stroke ratio remained constant over a wide blood pressure range, but at a lower diastolic blood pressure, there were substantially more MIs than strokes. An interaction between decreased diastolic pressure and history of revascularization was observed; low diastolic pressure was associated with a relatively lower risk for the primary outcome in patients with revascularization than in those without revascularization.

Limitations: This is a post hoc analysis of hypertensive patients with CAD.

Conclusions: The risk for the primary outcome, all-cause death, and MI, but not stroke, progressively increased with low diastolic blood pressure. Excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension.

Editors' Notes Context Experts debate the consequences of "excessive" lowering of diastolic pressure in patients with hypertension and coronary artery disease. Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease. The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infarction, with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg, that is, the lower the diastolic pressure, the higher the risk. Cautions The study examined associations between blood pressure and outcomes; it could not prove that the antihypertensive therapy that lowered diastolic pressure "too much" caused the adverse outcomes. —The Editors

 

Author and Article Information

From St. Luke's-Roosevelt Hospital, New York, New York; University of Milan, Milan, Italy; University of Florida, Gainesville, Florida; Abbott, Abbott Park, Illinois; Medizinische Klinik, Bielefeld, Germany; and Hôpital Brabois, University of Nancy, Nancy, France.

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{at}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.

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