Introduction

Top Abstract Introduction Participants and methods Results Discussion References

The management of patients with hypertension often focuses on drugs and other means of controlling blood pressure without adequate regard to their overall risk of morbidity and mortality from cardiovascular disease. The goal of treatment is to reduce the risk of stroke and heart disease and to prevent premature death. Hence a range of personal factors should be considered in assessing a patient's overall cardiovascular risk. A recent inquiry emphasised the benefits of using charts or scores for cardiovascular risk in getting treatment decisions made alongside realistic estimates of patient susceptibility to cardiovascular disease.¹

Other scoring methods already exist for assessing risk,^2-9 but ours has several particularly useful features: it focuses on patients with raised blood pressure, and it assesses an individual's overall risk for all cardiovascular diseases, including stroke, rather than just coronary heart disease. Although the guidelines from the World Health Organization and International Society of Hypertension usefully classify hypertensive patients from low risk to very high risk of cardiovascular disease,¹⁰ we present a more quantitative and discriminating risk score based on the mortality among participants in eight randomised controlled trials of antihypertensive treatment. We aimed to enable the calculation of risk of cardiovascular death within five years from a few personal factors.

	Participants and methods

Top Abstract Introduction Participants and methods Results Discussion References

The individual data analysis of antihypertensive intervention trials (INDANA) database includes all the major randomised trials of antihypertensive drugs versus placebo or no intervention for which individual patient data were available in 1995. ^{11 12} After exhaustive literature searches and personal inquiries we are confident that all such major trials are included. Here we assess data from all eight trials with results on mortality by intention to treat, totalling 47 008 participants of whom 3001 died (1639 from cardiovascular causes) during a mean 5.2 years of follow up (table 1).^13-20 The trials had differing eligibility criteria, and for the multiple risk factor intervention trial we focus only on the subset of participants with raised blood pressure.

Sixteen baseline factors were available in all datasets and had a priori plausibility as risk factors: age, sex, height, body mass index, current cigarette smoking, systolic and diastolic blood pressure, heart rate, concentrations of serum total cholesterol, serum creatinine and serum uric acid, previous myocardial infarction, previous stroke, diabetes, left ventricular hypertrophy detected by electrocardiography, and treatment group.

We fitted a multivariate Cox proportional hazards model, stratified by trial, for all 16 risk factors simultaneously, with cardiovascular death as outcome. We excluded body mass index, diastolic blood pressure, heart rate, and uric acid concentration, which were non-significant predictors. Systolic blood pressure was a stronger predictor than pulse pressure. For the remaining 12 factors we investigated possible statistical interactions in risk prediction. Thus we determined a final Cox model based on 1639 cardiovascular deaths in 47 088 participants with 12 risk factors and five interactions. No interactions with treatment group were strong enough to merit inclusion, and separate analyses for each trial broadly agreed with the overall model. We found no departures from linearity for quantitative risk factors.

We converted the Cox model predictor to an integer score. Briefly, the score is directly related to an individual's probability of death from cardiovascular disease within five years. This requires a reference sample from one country, and for this purpose we chose the 20 941 participants in the two UK Medical Research Council trials. We also wanted a zero score for an adult at very low riskthat is, a woman aged 35-39 with the healthiest category of each risk factor. Having grouped each factor into convenient intervals, such as every 10 mm Hg for systolic blood pressure, an individual's score increases by an integer amount for each risk factor level above the lowest risk category. Each integer amount is a rounding of the exact figure obtained from the proportional hazards model, so that the risk score is a simple addition of whole numbers. The estimated probability of death from cardiovascular disease within five years is equal to 10.99958^{exp (0.1 × risk score)}.

	Results

Top Abstract Introduction Participants and methods Results Discussion References

The risk score
Figure 1 presents the risk score for both men and women. Age is a particularly strong risk factora woman aged 60-64 has 23 extra points compared with a woman aged 35-39. Sex is also important, with men having 12 extra points. The gradient for risk according to age is slightly less noticeable for menthose aged 60-64 have 18 extra points (18+12=30 points). Cigarette smoking scores more points in women and at younger agesfor example, a female smoker aged 35-39 has 13 extra points compared with just 4 extra points for a male smoker aged 70-74. 

View larger version (34K): [in this window] [in a new window]   Fig 1.   Risk scores for cardiovascular disease in men and women

The chance of dying from cardiovascular disease
Figure 2 shows the exponential relation between the risk score and the probability of dying from cardiovascular disease in five years. Rates of cardiovascular death vary between trials and between communities in ways not fully explained by known risk factors. The curve in figure 2 relates to a British population, being based on cardiovascular death rates for participants in the two MRC trials. ^{15 16} The risk score itself, however, is derived from data on all participants in all eight trials.

Risk score by age and sex
Figure 3 shows the noticeable influence of age and sex on the risk score for the 20 941 participants in the two MRC trials. In general, the median age specific score for a man is similar to the median score for a woman 10 years older. Age affects risk: the median age specific score for a man corresponds to the score of a man at high risk who is 10 years younger and the score of a man at very low risk who is 10 years older. A score of 45, typical for a man aged 60-64, is achieved or exceeded by only 6% of men aged 50-54 but is exceeded by virtually all men aged 70-74; 45 is also the upper 90% point for women aged 60-64 and is achieved by no woman aged 50-54.

The risk factors
The list of risk factors chosen is not surprising, although their distributions vary between populations. Table 2 shows the distributions of risk factors for our subjects. Eligibility criteria differed between trials: one studied isolated systolic hypertension,¹⁹ whereas others primarily had an inclusion criterion for diastolic pressure. Hence the distribution of systolic blood pressure covers a wide range. The MRC trials excluded patients with previous stroke. Five trials were in elderly patients. ^{13 14 17 19 20} The distributions of cholesterol and creatinine concentrations and height are representative of developed countries in the West. The prevalence of diabetes is low, and it is an exclusion criterion in the MRC trials.

View larger version (18K): [in this window] [in a new window]   Fig 2.   Relation between risk score and probability of dying from cardiovascular disease in five years

View larger version (16K): [in this window] [in a new window]   Fig 3.   Distribution of risk scores by sex and age group.  is median score. Vertical lines indicate 20th, 80th, 90th, and 95th centiles. Horizontal line covers 2nd to 98th centile. Each score distribution is skewed to right, and there are two modes in each distribution, for non-smokers and smokers

Stroke, coronary heart disease, and all cause mortality
Separate predictions of stroke, coronary heart disease, and death from any cause are also relevant. Table 3 presents the results from the Cox model that led to the risk score for cardiovascular death, and also corresponding results for fatal coronary disease, fatal stroke, and all cause mortality.

	Discussion

Top Abstract Introduction Participants and methods Results Discussion References

The risk score developed by us is unique in being based on a large cohort of adults with moderately raised blood pressure, both treated and not treated with antihypertensive drugs, including both European and North American populations, and covering a wide age range. Thus the score has wide applicability in general practices and hypertension clinics, providing a simple means of quantifying a patient's risk of cardiovascular disease based on what should be routinely available information. The focus on overall cardiovascular risk, both of stroke and of coronary disease, ensures that a patient's overall wellbeing, including management of other cardiovascular risk factors such as smoking and lipid lowering, gets sufficient attention, keeping control of blood pressure and antihypertensive drug treatment in proper perspective.

The score is derived from people with blood pressure sufficiently raised to be included in a trial. However, the trials' differing eligibility criteria result in a wide spread of baseline blood pressures. Thus the score may be used in the general population, not just in people meeting specific criteria for hypertension. The score takes into account systolic but not diastolic blood pressure, because diastolic blood pressure does not independently predict cardiovascular risk. ^{21 22}

Mortality from cardiovascular disease varies between countries,²³which affects the generalisability of any risk score internationally. Although our data cover many developed countries, the problem remains of how to make a risk score specific to a country. Our solution has been to first obtain the most precisely estimated risk score from the whole sample of trials, but then focus on mortality in two UK trials when calculating the risk of cardiovascular disease for any individual. ^{16 17} Because the relative importance of risk factors remains similar in most developed countries, the main complication concerns differences in mortality from cardiovascular disease between countries. For instance, the United States and United Kingdom have rather similar death rates for cardiovascular disease, making the score readily applicable to the United States. In France the rates are much lower, so if the man in the example above were French his risk of cardiovascular death within five years would be substantially less than the calculated 19%. Also, within countries there are social and geographical inequalities and secular trends in cardiovascular disease, so any assessment of risk should take account of these less quantifiable influences on health.

Assessing individual risk
Individual risk assessment should be age and sex specific (fig 3). Risk of death from cardiovascular disease varies noticeably by age and sex (for example, the man aged 65 at lowest risk is at higher risk than the woman aged 50 at highest risk), and risk management strategies need to recognise this. It would be useful to obtain age and sex specific distributions of our risk score for representative samples of individuals from other countries.

Components of risk score
The risk score includes 11 risk factors for coronary heart disease and stroke. Age, sex, and cigarette smoking are the strongest predictors. The sex difference narrows with age, and the impact of smoking is more noticeable in women and at younger ages. Serum total cholesterol concentration and systolic blood pressure have similar predictive strength in men, but cholesterol concentration is less important for women because their risk of coronary disease is much lower. Raised creatinine concentration²⁴ and short stature²⁵ are both established highly significant risk factors for coronary disease and stroke, and although not present in previous risk scores should be included here. Diabetes is a more noticeable predictor of cardiovascular disease in women than it is in men,²⁶ and history of stroke, myocardial infarction, and left ventricular hypertrophy are obvious factors to include. Other risk factors, such as more detailed assessment of blood lipids (for example, high density lipoprotein cholesterol and triglycerides) or presence of angina or intermittent claudication, could in principle be included but were not available in all our trials, and there is a danger of making risk scores too detailed and complicated.