There remains a paucity of data regarding the presence of a quiescent period of coronary disease sufficient to cause inducible ischaemia in persons with a family history of premature coronary disease. Although a small number of studies in apparently healthy males 40–70 years of age found the prevalence to be between 2.5 and 14%,28,29
we found a considerably higher prevalence of inducible ischaemia in healthy asymptomatic siblings of persons with early onset CAD. The length of time from the identification of ischaemia to the occurrence of a clinically manifest CAD outcome was quite long, a mean of 8 years. While it is known that latent atherosclerotic disease is present for long periods of time, this long period of inducible ischaemia in siblings prior to a clinical CAD event is a novel finding that provides a stimulus for reconsidering the importance of family history in establishing therapeutic prevention thresholds and goal levels of risk factors, particularly among male siblings. As anticipated, CAD risk factors were highly prevalent and were significantly associated with both inducible ischaemia and incident CAD events.
In our study, excluding all siblings who would already be identified as a CAD risk equivalent because of diabetes or a FRS of ≥20%, the prevalence of inducible ischaemia was high among males ≥40 years of age. Similarly, high rates of incident CAD events were observed beginning at 40 years of age, even among men without ischaemia. These findings are similar to those observed in diabetics of comparable age30,31
and on that basis alone appear to warrant similar thresholds for the initiation of aggressive preventive interventions according to published guidelines in the USA32
and in Europe.33
Thus, brothers of persons with early onset CAD have both a high prevalence of early inducible ischaemia and also bear a sufficiently high enough risk of CAD to warrant aggressive preventive therapies without undergoing stress perfusion imaging. Additionally, risk factor levels are high enough to suggest a potential benefit.
The issue is far less clear among women and presents a conundrum with regard to recommendations. Rates of incident CAD were 20% or higher only among those with inducible ischaemia, but beginning as early as 40 years of age. It would be tempting to recommend that stress perfusion imaging be considered for more precise risk stratification, but given the low prevalence of inducible ischaemia in women, one would have to consider the cost to the medical care system and the possible effects of additional radiation exposure. In context, for every 100 female siblings aged 50–59 years undergoing stress perfusion imaging to identify inducible ischaemia, only 4.6 individuals would have ischaemia and go on to have an event over the subsequent 10 years. Thus, given the overall pro-health benefits of therapeutic lifestyle interventions, at a minimum, adopting those recommendations in women with a family history or premature CAD appears to be justified. Beyond that, more aggressive risk modification would need to be tailored to the unique risk profiles of women with a family history. Clinicians may consider nuclear stress testing in sisters of CAD patients where family history is particularly strong and/or unique risk factor profiles are present that warrant attention. The yield of exercise testing without nuclear perfusion imaging is very low in both sexes.
Concerns about the negative sequelae of broadly applied aggressive preventive interventions in male siblings need to be balanced with potential benefits. Aspirin is associated with intracranial34
and gastrointestinal bleeding35
but its use for primary prevention in men is highly beneficial, demonstrating a significant risk reduction in cardiovascular events.36
Based on the risk/benefit ratio, the US Preventive Services Task Force recommends aspirin use in men with a 10-year risk of cardiovascular events >6%, unless contraindicated.37
By this standard, most male siblings ≥40 years of age from high-risk families would fall into this category where the benefits are expected to outweigh the risks. In Europe, aspirin prophylaxis for primary prevention is more controversial38
with recommended use in asymptomatic individuals only if their 10-year risk of total CAD mortality is >10% and blood pressure is controlled as closely as possible to goal.4
Under these contingencies, based on our findings, most male siblings 40 years of age or older, would be eligible for aspirin chemoprophylaxis.
Statin therapy used for primary prevention of CAD events was recently shown to be beneficial in a large scale meta-analysis of randomized trials.39
In males without known CAD but with a 10-year risk for MI or stroke of ≥20%, the number needed to treat to prevent one event over 5 years is significantly less than the number associated with acute renal failure, cataracts, liver dysfunction, or myopathy.40
Guidelines released in the USA41
and in Europe4
recommend a goal LDL cholesterol level <2.5 mmol/L in asymptomatic people at high risk of developing cardiovascular events. Few siblings in our study were close to that goal level at screening. Low-density lipoprotein cholesterol levels were high and associated with both the ischaemia substrate for CAD and with CAD events.
While there clearly is significant predictive value of stress perfusion testing in our study, men over 40 years of age had very high rates of incident CAD, even in the absence of ischaemia. This creates a primary prevention scenario whereby the testing has few to no therapeutic implications in asymptomatic individuals. In women, the likelihood of finding inducible ischaemia is simply too low to warrant such testing on a routine basis.