How to Intensify Treatment in Older Patients With Hypertension: Is There a Single Answer?

Randomized trials show that half-dose dual combination therapies for hypertension reduce blood pressure (BP) more than full-dose monotherapies, with no more adverse effects (1). Indeed, combining 2 drugs has an additive effect on BP reduction, whereas increasing the dose of a drug is less than additive (2): A half dose is only 25% less potent than a full dose. Under these assumptions, the expected potency of antihypertensive drug combinations can be approximated (Table). For example, the combination of 2 drugs at half dose is expected to be 50% more potent than a single drug at full dose. Using half doses also reduces the adverse effects of thiazide diuretics and calciumchannel blockers (2), and combination with a renin–angiotensin system blocker further reduces some of them, such as thiazide-induced hypokalemia and calcium-channel blocker– inducedperipheral edema. The main drawback of dual combination therapies is the number of pills needed. However, many can be prescribed as single-pill combinations (SPCs), with improved adherence and persistence compared with free-equivalent combinations (3). Large cohorts of real-life patients have shown that initiating hypertension treatment with a drug combination (usually as an SPC), rather than a single drug, is associated with fewer treatment discontinuations (4), better BP control (5), and ultimately a lower risk for cardiovascular events (6, 7). The evidence available to guide intensification when treated patients do not reach their BP goal is more limited. When all existing drugs are already at full dose, we add a new drug. But when at least 1 drug is not at full dose, should we add a new drug or first maximize doses of existing drugs? The pharmacologic rationale suggests that adding a half-dose new drug is more potent with fewer adverse effects, but the use of SPCs is not always possible in this case, and more pills can lead to poorer adherence and treatment discontinuation. Aubert and colleagues' study (8) addresses the question of treatment intensification in patients with hypertension. No fewer than 178562 veterans with systolic BP above 130 mm Hg and at least 1 antihypertensive drug not at full dose had their antihypertensive regimen intensified: 45575 (26%) by drug addition and 132987 (74%) by dose maximization. Outcomes were then compared after adjustment for baseline characteristics. Drug addition was less frequently sustained at 3 months than dose maximization (49.8% vs. 65.0%), but the 12-month mean decrease in systolic BP was nonetheless 1.1 mm Hg larger (5.6 vs. 4.5 mmHg). This study included a vast number of elderly patients, who are underrepresented in clinical trials. The authors used sophisticated statistical methods to emulate a clinical trial in this observational cohort, but the results remain vulnerable to bias and confounding. For example, the assessment of BP relied on unstandardized office measurements. This adds noise to the outcome data and might bias the results in unpredictable ways, especially because white-coat hypertension is common in this age group (9). However, the main shortcoming of the study lies in the broad spectrum of baseline situations. The logic of treatment intensification differs with the baseline number and doses of antihypertensive drugs, number of pills per day, BP level, and clinical condition, including comorbid conditions and fitness (especially in older patients). Encompassing such a heterogeneous case mix prevents definitive conclusions on how best to intensify treatment in patients with uncontrolled hypertension, in general or in any given situation. Consider a patient who is not at his BP goal while receiving an SPC with 2 half-dose drugs (combination potency of 150% in 1 pill; see the Table). We could favor maximizing the dose of the 2 drugs of the SPC (potency of 200% in 1 pill) rather than adding a third drug at half dose (potency of 225% but 2 pills). Staying with a single pill may offset the more limited potency increase and warrants an attempt. Now consider the same patient not at his goal while receiving an SPC with 1 full-dose and 1 half-dose drug (potency of 175% in 1 pill). Here we could first favor adding a third drug at half dose (2 pills but potency of 250%) rather than maximizing the second drug of the existing SPC (1 pill but potency of 200%). The larger potency increase may be worth the burden of adding 1 pill, provided the patient agrees with this strategy. These 2 oversimplified examples only scratch the surface of diverse situations requiring individualized and shared decisionmaking. Nonetheless, 2 results must be stressed. First, whatever the chosen strategy, treatment intensification leads to large BP decreases in patients who need it the most. Figure 3 of Aubert and colleagues' article shows that the mean 12-month decrease in systolic BP is about 8 mm Hg in patients with baseline systolic BP between 140 and 160 mm Hg and about 20 mm Hg in those with baseline systolic BP over 160 mmHg. Second, the 2 intensification strategies are associated with similar 12-month BP decreases in the emulated intention-to-treat analysis. In this analysis, mean BP decrease is the compound result of persistence and BPlowering potency. A similar mean BP decrease despite lower persistence is, therefore, confirmatory evidence that drug addition is more potent than dose maximization in those who persist. When a large BP decrease is needed, drug addition should be preferred together with promoting persistence—for example, with SPCs and patient education (3, 10). In practice, this study provides support to several general principles of antihypertensive drug prescription. When intensification is indicated, we should not waste