Smoking cessation in individuals with Familial Hypercholesterolemia was associated with considerable decrease of the risk of cardiovascular atherosclerotic events. The risk reduction proved to follow a linear pattern over time, but it was difficult to distinguish this from nonlinear patterns. The slope of the linear reduction-line was estimated as 0.11 univariately, and 0.18 when corrected for confounders. This means that it took 1/0.18 ≈ 6 to 1/0.11 ≈ 9 years after cessation before the risk was reduced to the level of persons who never smoked.

The risk of atherosclerotic events due to smoking was estimated at 2.1 (95% ci: 1.5; 2.9), which coincides with many results in the literature [11–13], or only slightly higher [14–16]. We found only weak relationships between atherosclerotic events and number of cigarettes smoked, but this is probably due to the unreliability of these data (20 percent of the patients were not willing or able to quantify the number cigarettes smoked).

The estimate that it takes six to nine years after smoking cessation before the risk of atherosclerotic events is reduced to the level of persons who never smoked, agrees with findings by others. McElduff et al [6] found that the excess risk for a major coronary event due to smoking disappeared about four to six years after smoking-cessation in a population-based case-control study of 5,572 cases and 6,268 controls. Wannamethee et al [11] observed a similar stroke-risk reduction in 7,735 middle aged men, although the speed of reduction depended on smoking-quantity. In a population-based cohort of 758 women, Witteman et al [12] found that the excess risk for calcific deposits in the abdominal aorta was increased up to 10 years after cessation. Negri et al [13] also observed that it took up to 10 years after cessation before risk of acute myocardial infarction was reduced to the level of never-smokers in 916 cases with acute myocardial infarction and 1106 controls. A slightly longer period was observed by Kawachi et al [17] in the Nurses' Health Study among 117,001 nurses; they found that the risk of total coronary heart disease reduced by one third within 2 years of cessation, but afterwards it took 10 to 14 years for this excess risk to return to the level of those who never smoked. Chaturvedi et al [18] also observed a longer period (> 10 years) for the excess mortality-risk returned to normal in 4,427 individuals with diabetes. Omenn et al [19] observed that this excess risk was increased up to 20 years after cessation in 21,112 men and women evaluated with coronary angiography. A far shorter period of three years was found, however, by Rea et al [14] in a cohort of 2,169 persons who survived after first myocardial infarction. The variation in speed of risk-reduction after cessation between all these studies is probably caused by the differences in populations. In our population of familial hypercholesterolemia atherosclerosis is known to develop earlier in live with an increased speed of progression. It is possible that exposure to smoking has a bigger impact, and therefor takes longer to diminish. But next to differences in populations between the above mentioned studies, the variation is, in our view, also illustration of the difficulty to estimate the pattern with which excess risk reduces after cessation. Moreover, the lifetime smoking history was reconstructed from retrospective review of medical records and patient recall -both are known to be of poor quality-, and this will also influence outcome of our study.

We used the Cox regression model with smoking as a time-dependent covariate for statistical analysis of the risk after smoking-cessation. The time dependence of the excess-risk after smoking-cessation was modelled with a linear or exponential decaying trend; these two models were very flexible and capable of many possible patterns, but even more flexibility may be obtained with nonparametric techniques such as splines, kernels functions or lowess regression. We doubt whether such techniques offer much more insight because we found that it was already very difficult to distinguish different linear and (parametric) nonlinear patterns; even more irregular patterns will be even harder to distinguish. Others [14, 15] used data-driven methods to estimate the excess-risk in ex-smokers in one, two, three, and up to ten years after cessation. Such statistical modelling is nonparametric in a way, since no assumption is made on the way the risk reduces after smoking-cessation, but this approach requires more parameters to be estimated, and therefore introduces more uncertainty.

We used a bootstrap approach to account for the uncertainty regarding the smoking-risk reduction after cessation. This offers the possibility to use standard statistical packages and tools for analyses. In our data the uncertainty on the smoking-risk-reduction after cessation had little effect on the estimates of the log-hazard ratio's of the Cox model of smoking itself, and of other covariates in the model, but this is probably due to the relatively large sample size and event number in our sample. Finally, we checked the proportional hazards assumption of the Cox regression model with regard to smoking by extending the model with the interaction of smoking and log(time), and found little evidence for violation of this assumption (*p* = 0.88). This is somewhat surprising since the relative risk of atherosclerotic events due to smoking is strongly related to age ([20]), but this may be due to the somewhat smaller age-distribution in our study.

In conclusion, smoking should be treated as a time-dependent risk factor when using lifetime data. Moreover, the risk reduction of smoking after cessation should be taken into account.