Different guidelines generate nonuniform recommendations for first-line therapy in patients with uncomplicated hypertension, despite use of the same evidence base. While there may be various explanations for this (12
), we sought to determine whether consideration of cost or cost effectiveness played a role. It is surprising that in the three guidelines in which recommendations appear to be influenced by cost or cost-effectiveness considerations, the recommendations still have major differences. The only guideline that integrates findings from a primary economic evaluation (9
) does not list thiazide diuretics, the drug class with the lowest acquisition costs, as the single preferred agent. Furthermore, two recently published high-quality economic evaluations performed by major government-associated HTA agencies came to differing conclusions regarding the attractiveness of treatment with calcium channel blockers. This review identifies several factors that are key drivers of cost and cost effectiveness, including relative drug acquisition costs, impact on development of associated conditions, and chronic adverse drug side effects affecting HRQOL of the various drug classes.
Differences in drug acquisition costs among antihypertensive classes can be a major driver of both cost and cost effectiveness. This is evident in the Canadian economic evaluation, where annual drug costs for other classes were seven to 27 times higher than a thiazide diuretic (). When very large cost differences exist, more expensive agents need to demonstrate a substantial advantage over thiazide diuretics in health outcomes and attendant downstream health care costs to be considered attractive within a cost-effectiveness framework. While a cost-minimization approach (where effectiveness is assumed to be equal and the lowest cost treatment strategy is deemed optimal) has been criticized (13
), this approach may be reasonable for uncomplicated hypertension because effectiveness has generally been found to be similar between drug classes. Indeed, this framework has been informally applied in some of the identified guidelines, leading to recommendations for thiazide diuretics as first-line therapy in uncomplicated patients.
However, a cost-minimization approach is not appropriate when the relative differences in annual drug costs among classes falls, as small differences in effectiveness begin to have a greater impact on conclusions. In the UK economic evaluation, where the cost of alternate medication classes are only one- to fivefold greater than thiazide diuretics, thiazides were not considered to be the most cost-effective agents in uncomplicated hypertension and, under some scenarios, ACE inhibitors or angiotensin receptor blockers became a cost-effective alternative. These analyses were driven by the relative differences in some drug classes on development of heart failure and diabetes, as well as different assumptions on the baseline risk of developing these conditions. While this reflects drug pricing in the UK at the time of the analysis, this scenario may also occur in other jurisdictions as drugs become generic and prices fall. For example, the cost of the commonly used dihydropyridine calcium channel blocker amlodipine has decreased by 50% from 2006 to 2009 in Alberta (14
), leading to substantially lower estimated annual drug acquisition costs relative to thiazide diuretics (). It should also be noted that actual drug acquisition costs may vary within Canada (15
), which may lead to differing optimal approaches between and within each province. As such, it is important to update economic evaluations with geographically specific data to reflect current cost realities for each jurisdiction.
Relative annual costs of antihypertensive treatment in Alberta in 2006 and 2009
Certain classes of medications have been found to have an advantage over others with respect to development of associated conditions such as heart failure, stroke and diabetes. While the relative effect size is of moderate magnitude (20% to 40% difference), the relatively low absolute risk of development of de novo conditions in subjects with uncomplicated hypertension translates into small absolute effects. However, the UK economic evaluation confirms that the impact on development of these conditions is important. In addition, the efficacy among drug classes may vary by age or ethnicity (17
) and, therefore, may also impact economic conclusions. The baseline risk of developing heart failure or diabetes altered conclusions due to the HRQOL decrement and health care costs associated with these conditions. Because calcium channel blockers are associated with an increased risk of heart failure but a lower risk of diabetes compared with thiazide diuretics, altering the risk of development over a small range (0% to 3%) led to changes. These were not seen in the Canadian analysis, most likely due to much greater differences in drug costs (although diabetes was not considered as a health state in the Canadian model).
In settings with smaller differences in cost among the drug classes, considerations other than relative effectiveness may alter results. The UK model suggested that while the quality of life decrements associated with chronic pharmacological therapy for hypertension are unknown, relatively small changes for all agents and between agents can alter results. While not specifically evaluated in either model, factors such as side effects that impact persistence (adherence) of therapy may also have a substantial impact on cost-effectiveness conclusions (18
). Observational studies have found that persistence is lowest with diuretics and beta-blockers, and is higher with angiotensin receptor blockers and ACE inhibitors, which may impact the relative cost effectiveness of therapy (19
). It is also possible that other potential drivers of cost effectiveness may play a role, such as costs of laboratory monitoring with each medication class (22
) or other potential side effects that may lead to hospitalization such as hyponatremia or hyperkalemia, neither of which were included in the two reports.
The present review has several limitations that warrant acknowledgment. First, given the lack of information in guidelines, it was often not clear to what extent cost and cost effectiveness played a role in formulating recommendations. This contrasts sharply with more explicit descriptions of processes for how efficacy evidence is used in the creation of recommendations for practice guidelines. Second, the review of economic evaluations was limited to a single database, and did not include other peer-reviewed publications. However, this database captures HTAs conducted by members of the International Network of Agencies for Health Technology Assessment and other major HTA organizations, which are likely to be used to influence health care policy and decision making. In addition, we did not have access to the economic models used, and the identification of key drivers of cost effectiveness was limited to what was presented by the authors and our interpretation. For example, cases of heart failure and diabetes attributed to medication use were assumed to have the same quality of life and cost impact as typical cases, and we were not able to further test this and other assumptions used in the models. We also could not definitively determine to what extent drug cost differences, or inclusion or exclusion of the health state of diabetes altered study conclusions. In addition, the models only considered monotherapy; however, most patients with hypertension require at least one agent to meet optimal blood pressure targets (21
). The choice of subsequent lines of therapy, if varying in effectiveness and costs, may also impact ranking conclusions.
While information from cost-effectiveness studies is rarely formally integrated into guideline development (25
), given the reality of finite health care resources, it is imperative to explicitly integrate findings from such analyses into recommendations to ensure health system sustainability. Relying on drug acquisition costs alone may not be reliable to estimate cost effectiveness, particularly in jurisdictions where the relative differences among drug class costs have decreased. In these settings, differential effects on development of comorbid conditions such as heart failure and diabetes, medication-related changes in HRQOL, or persistence with therapy may be important factors. We advocate further study on the relative differences between drug classes on outcomes, quality of life and adherence (20
), particularly for different patient subgroups (26
), to determine optimal and efficient treatment. Identification of key drivers of cost effectiveness will assist in the interpretation of current economic evaluations, and should be incorporated into future economic evaluations that inform treatment guidelines.