Discussion
This population-based nationwide study of nearly 4000 AD patients during a 10-year period demonstrated that 96% of the patients were on antihypertensive treatment within a year from discharge. The use of statins was associated with higher long-term survival in patients managed medically, both in women and in men. The association between drug use and long-term survival for the various drugs differed between patients undergoing repair and those being managed only medically; ARBs and beta blockers were favourable in surgically managed patients, whereas ACE inhibitors and CCBs were favourable in medical management.
Aggressive lowering of systolic blood pressure has long been the mainstay in the acute management of AD. The best antihypertensive medication strategy and how to manage hypertension in patients with chronic AD, however, are still matters of debate.15 The ESVS guidelines recommend systolic blood pressure below 130 mm Hg and diastolic pressure below 85 mm Hg, with beta blockers as first-line treatment.7 The present study confirmed the wide use of antihypertensive medication in general and beta blockers in particular in AD patients, with 96% of the patients being on antihypertensive medication at discharge. In 90% of the cases a beta blocker was used, mostly combined with additional drugs. In the acute phase, resistant hypertension frequently requires multiple drugs, in contrast to the chronic stage of the disease, when the resistant hypertension tends to resolve. Nevertheless, within the first year, 46% of the patients were on ≥4 antihypertensives, which is in accordance with earlier reports.16 17
Beta blockers and ARBs were associated with higher long-term survival in patients undergoing surgical repair, whereas in the medical strategy group, CCBs and ACE inhibitors were associated with better outcome. This finding is in agreement with an IRAD report demonstrating survival benefit of beta blockers in surgically treated TAD patients and an association between CCB use and higher survival in medically managed TBD patients.18 Similar to the IRAD data, it is most likely that the majority of patients subjected to medical treatment in the present report had uncomplicated TBD.13 Single-centre studies have shown reduction of aortic events in acute and chronic TBD by using beta blockers.9 19 A recent Taiwanese register study demonstrated lower risk of hospital readmission and all-cause mortality in acute AD patients receiving a beta blocker, ACE inhibitor or ARB after discharge from the primary hospitalisation.20 One potential weakness of the demonstrated favourable effect of beta blockers in surgically manged patients is that the study design does not allow further analysis of the mechanisms. Moreover, roughly 1 in 10 patients of both surgically and medically managed patients, respectively, did not receive beta blockers, but the reason for that decision is unknown. The role of beta blockers in chronic TBD needs to be evaluated in future studies. In TBD patients who experience side effects from beta blockers, one could consider shifting to other antihypertensive drugs, especially since the presumed superiority of beta blockers has not been confirmed in a randomised trial.15 21 The role of CCBs in patients with aortic dissection is uncertain. It was recently reported that in patients with Marfan syndrome, treatment with CCBs was associated with aortic dissection and aortic surgery during follow-up.22 In this report and in IRAD, medically managed patients did benefit from treatment with CCBs. The majority of these patients can be assumed to have had uncomplicated TBD and presumably very few of them had genetic disorders. Moreover, treatment with CCBs has been associated with decreased aortic expansion in patients with uncomplicated TBD.23 The diverging findings point at the need of further studies on the role of CCBs in AD patients with different aetiologies managed with different strategies.
Statins are recommended to all patients with peripheral arterial disease, according to the ESVS peripheral arterial diseases guidelines.24 The ESVS suggests treatment of hyperlipidaemia in patients with chronic AD but without further specific recommendations.7 Fairly recently, statin therapy was shown to improve long-term survival in patients undergoing abdominal aortic aneurysm (AAA) repair.25 To date, to our knowledge, no such evidence exists regarding patients with AD. In the JUPITER trial, 20 mg daily of the statin rosuvastatin was found to reduce the incidence of major cardiovascular events in patients without marked hyperlipidaemia but with elevated high-sensitivity C reactive protein (CRP) levels.26 Acute AD patients have been shown to exhibit an inflammatory reaction, manifested by elevated biomarkers, including CRP.27 A further meta-analysis indicated that the preventive effect of statins in men and women at equal cardiovascular disease risk was similar.28 In the present study, a minority were treated with statins prior to admission, whereas almost half of the patients were on statins within a year from discharge, pointing at the lack of evidence of statin use in AD patients. Treatment with statins after discharge from hospitalisation was associated with higher long-term survival. In subgroup analyses, the association was confirmed in medically managed patients, both in women and in men, but not in patients undergoing surgical repair. As statins have been shown to improve the long-term outcome of open and endovascular AAA repair, the absence of such an effect in association with AD surgery raises further questions.25 It is plausible that lower degree of atherosclerosis in AD patients than in aneurysm patients influenced the importance of statins, mainly in patients with TAD who constitute the absolute majority of surgically managed patients in the present study. The pivotal role of antiplatelet therapy in coronary heart disease and stroke and in AAA repair was not exhibited in this large group of AD patients, possibly further suggesting that acute AD is not primarily an atherosclerotic disease.29
We did observe some treatment strategy changes during the second 5-year study period, 2011–2015, compared with the first 5 years of the study. ACE inhibitors became less common, whereas ARBs, CCBs and diuretics were more commonly used in the later period. In comparison, during the period 2005–2016, except for decreased use of diuretics, antihypertensive treatment strategies in stroke survivors in the USA did not change.30 Since treatment with four or more antihypertensive agents became more common in the second 5-year period, it is possible that the increased use of ARBs, CCBs and diuretics was a result of multiple-drug use rather than just a shift from other drug types.
The aims of secondary preventive strategies in AD patients are to prevent dilatation and late aortic-related death as well as death from other cardiovascular diseases. In uncomplicated TBD, there is ongoing debate whether or not to prophylactically cover the entry site and adjacent aortic segment with a stent graft, in addition to providing the patients with BMT. An important factor to consider in assessment of the efficacy of medical management is adherence to antihypertensive medication. A study of patients with chronic TBD showed that less than half (43%) reported high degree of adherence and 21% reported low adherence.31 Analogously, in a study of 65-year-old Swedish men with screening-detected carotid plaque or asymptomatic carotid artery stenosis, the majority were neither treated with statins nor antiplatelet agents at follow-up 5 years later.32
In the present study, there are no data on blood pressure levels or medication adherence. Nevertheless, 96% of all the discharged patients had filled prescriptions of one or more antihypertensive drugs, which is highly encouraging in terms of adherence. The study is further limited by the absence of data on lipid levels, renal function, haemoglobin, platelet count and liver function as well as information on the main indication for each drug; for example, an ACE inhibitor could be prescribed for either hypertension or heart failure or both, that is, confounding by indication may be present. Details on drug types and doses from each drug group were not available. The retrospective register-based design and dependence on valid ICD coding of AD are also potential limitations, including the inability to distinguish between TAD and TBD among medically managed patients and the incapacity to differentiate between various dissection aetiologies.13 As treatment strategies, including medical management, of AD patients may vary based on aetiology, the lack of information on aetiology is a limitation to the generalisability of the findings. The SPDR includes only dispensed prescription drugs; it is unique in that PINs are included, enabling linkage with other registers. The SPDR has undergone thorough scrutiny.33 It would be of great interest to link drug dispensing data from the register to patient-reported intake to learn more about adherence to medication and the overall quality of drug treatment.
A strength of this study is the population-based design with inclusion of nearly 4000 patients over a 10-year period. The analysis of filled prescriptions is likely to provide a good marker of drug intake as it is probable that once drugs are dispensed, they are to a high degree also taken by the patients.
In summary, this large population-based study demonstrated two key perspectives on pharmacological treatment of patients with AD. First, the beneficial effects of beta blockers in the chronic stage of the disease are challenged by the lack of positive association with long-term survival in medically managed patients in this study. Second, it is striking that previously established positive effects of statins on survival in other cardiovascular patient groups seem to be true also for patients with AD, and statins should perhaps be recommended to all medically managed AD patients. Several results may be hypothesis generating for future randomised controlled trials further assessing the impact of statins in surgically managed patients as well as optimal antihypertensive therapy in the chronic stage of the disease.