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Relationships of different types of event to cardiovascular death in trials of antihypertensive treatment: an aid to definition of total cardiovascular disease risk in hypertension

Zambon, Antonellaa; Arfè, Andreaa; Corrao, Giovannia; Zanchetti, Albertob

doi: 10.1097/HJH.0000000000000077
ORIGINAL PAPERS: Cardiovascular risk

Background and objective: Guidelines for management of cardiovascular diseases stratify absolute cardiovascular risk into categories with a high-risk threshold defined at a 20% cardiovascular events risk in 10 years, but it is unclear whether only major events or the Framingham-extended definition should be considered. The 2013 ESH-ESC hypertension guidelines, instead, define cardiovascular risk as a risk of cardiovascular death in 10 years, as in the SCORE model, setting the threshold for high risk at the 5% level. It would be therefore convenient to know the quantitative relationship between the risks of the different outcomes adopted by the different guidelines, especially because some outcome definitions include serious nonfatal cardiovascular events relevant in cardiovascular prevention. We have therefore analysed these relationships in trials of antihypertensive therapy as an aid to defining total cardiovascular risk in hypertensive patients.

Design and methods: Sixty-one trials were identified, and 51 retained for analysis of the relationship of cardiovascular death to the incidence of all-cause death, major cardiovascular events and inclusive (Framingham) cardiovascular events. The relationship between cardiovascular death rates and each type of event rates was explored by fitting flexible regression models.

Results: The included trials provided 15 164 cardiovascular deaths and 1 674 427 patient-years. The relation of each event rate to cardiovascular death rate was best explained by a model considering the logarithm of each event rate as a dependent variable and the logarithm of cardiovascular death rate as a predictor. Mean patients’ age and treatment were also predictors, but to a minor extent. The increase of the incidence rates of all types of events was less steep the higher the CV death rate: the rate ratios of all-cause death to cardiovascular death were 2.2, 1.9 and 1.8 at low-moderate (cardiovascular death <5% in 10 years), high (cardiovascular death 5% to <10%) and very high risk (cardiovascular death ≥10%), respectively; the rate ratios of major cardiovascular events to cardiovascular death were 3.9, 2.7, 2.3 and the rate ratios of extended cardiovascular events to cardiovascular death were 8.4, 5.6 and 4.6, respectively. Ratios only slightly changed when 12 trials of secondary prevention were excluded.

Conclusion: Ratios of various event rates to cardiovascular death rate vary with cardiovascular disease severity, cardiovascular mortality representing an increasing proportion of total cardiovascular risk when the former is higher. From the models, a total risk can be estimated in groups of hypertensive patients whose cardiovascular death risk is calculated by the SCORE model.

aDepartment of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano Bicocca

bIstituto Auxologico Italiano, University of Milan, Milan, Italy

Correspondence to Alberto Zanchetti, MD, Istituto Auxologico Italiano, Via L. Ariosto 13, 20145 Milan, Italy. Tel: +39 02 619112237; fax: +39 02 619112294; e-mail:

Abbreviations: ABCD-NT, Appropriate Blood pressure Control in Diabetes-Normotensive patients; ACCOMPLISH, Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension; ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACEI, angiotensin converting enzyme inhibitor; ACTION, A Coronary Disease Trial Investigating Outcome with Nifedipine Gastrointestinal therapeutic system; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; Australian-2, Australian Blood Pressure Council Trial 2; Australian-Mild, Australian Trial on Mild Hypertension; BB, beta-blocker; [C], calculated with less precise approximation; C, calculated; CA, calcium antagonist; CAMELOT, Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis; CAPPP, Captopril Prevention Project; CHD, coronary heart disease; CKD, chronic kidney disease; CONVINCE, Controlled Onset Verapamil Investigation of CV Endpoints; Coope, Randomized Trial of Treatment of Hypertension of CV Elderly Patients in Primary Care; CV, cardiovascular; CVD, cardiovascular disease; CVE, cardiovascular event; D, diuretic; DBP, diastolic blood pressure; DM, diabetes mellitus; DREAM, Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication; DUTCH-TIA, Dutch Transient Ischemic Attack Trial; ECG, electrocardiogram; ELSA, European Lacidipine Study on Atherosclerosis; EUROPA, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease; EWPHE, European Working Party on High Blood Pressure in the Elderly; FEVER, Felodipine Event Reduction study; GITS, gastrointestinal therapeutic system; HAPPHY, Heart Attack Primary Prevention on Hypertension trial; HCTZ, hydrochlorothiazide; HDFP, Hypertension Detection and Follow-up Program; HF, heart failure; HOPE, Heart Outcomes Prevention Evaluation; hosp, hospitalized; HOT, Hypertension Optimal Treatment; HT, hypertension; HYVET, Hypertension in the Very Elderly Trial; IDNT, Irbesartan Diabetic Nephropathy Trial; IHD, ischaemic heart disease; INSIGHT, International Nifedipine GITS Study-Intervention as a Goal in Hypertension Treatment; INVEST, International Verapamil SR/Trandolapril study; IPPPSH, International Prospective Primary Prevention Study in Hypertension; ISH, isolated systolic hypertension; JATOS, Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; JIKEI, Jikei Heart Study; LIFE, Losartan Intervention For Endpoint Reduction in Hypertensives; MI, myocardial infarction; MRC-M, Medical Research Council Trial of Treatment of Mild Hypertension; MRC-O, Medical Research Council Trial of Treatment of Hypertension in Older Adults; NA, not assessable; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Study; NORDIL, Nordic Diltiazem Intervention Study; OD, organ damage; ON-TARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint trial; OSLO, Oslo Trial on Treatment of Mild Hypertension; PAD, peripheral artery disease; PATE-HT, Practitioner's Trial on the Efficacy of Antihypertensive Treatment in the Elderly Hypertension; PATS, Post-stroke Antihypertensive Treatment Study; PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition; PROFESS, Prevention Regimen for Effectively Avoiding Secondary Strokes; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; R, reported; revasc, revascularization; RF, risk factor; SBP, systolic blood pressure; SCOPE, Study on Cognition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; STOP, Swedish Trial in Old Patients with Hypertension; STOP-2, the Second Swedish Trial in Old Patients with Hypertension; SystChina, Systolic Hypertension in the Elderly Chinese Trial; SystEur, Systolic Hypertension in Europe Trial; TIA, transient ischaemic attack; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease; UKPDS, United Kingdom Prospective Diabetes Study; VALISH, Valsartan in Elderly Isolated Systolic Hypertension Study

Received 2 August, 2013

Accepted 14 November, 2013

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