Analysis of Recent Papers in Hypertension

A Simplified algorithm with fixed‐dose combinations as initial therapy provides improved blood pressure control compared with usual guideline‐based care in Canada: The STITCH Trial

A number of barriers to improved blood pressure (BP) control have been identified, but strategies to overcome these barriers remain largely unimplemented. The Simplified Treatment Intervention to Control Hypertension (STITCH) study was a cluster‐randomized, prospective, industry‐supported, but independent investigator‐designed and ‐implemented, trial to compare the effectiveness of a simplified stepped‐care treatment algorithm using initial fixed‐dose single‐pill combination therapy with a usual guideline–based approach that included initial monotherapy in community‐based family practice settings in Canada.

To minimize the risk of treatment contamination at the patient level, individual practitioners rather than individual patients were randomized to either guideline‐based care (based on the Canadian Hypertension Education Program [CHEP]) or care based on an algorithm utilizing initial fixed‐dose combination therapy that was designed specifically for this trial (STITCH algorithm). The study was conducted at 45 solo family physician practices in Ontario, Canada, between February 2005 and January 2007. To be eligible, practices had to identify at least 50 patients during the screening process with untreated or partially treated hypertension that was uncontrolled (defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg in patients without diabetes or systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg in patients with type 2 diabetes mellitus). Ninety‐six practices expressed interest and were evaluated for eligibility; 93 were selected for randomization. Thirty‐five of the original 93 practices did not identify a sufficient number of patients and, after randomization, a number of practitioners declined further participation and were withdrawn. This left a total of 45 practices eligible for analysis, 27 randomized to guideline‐based care according to the CHEP algorithm and 18 practices randomized to STITCH care.

At each participating practice, eligible patients included those who were at least 18 years of age and had uncontrolled hypertension (based on the definition above). Both treated and untreated patients were eligible. Exclusion criteria included ischemic heart disease, atrial fibrillation, peripheral vascular disease, stroke, stage 4 or 5 chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m²), or concurrent participation in another clinical trial. At each practice, patients were consecutively enrolled as they arrived for their usual office visits; a maximum of 50 enrolled patients were allowed from each practice. A total of 2104 patients were enrolled, of whom 49% were already being treated with antihypertensive medication at their baseline assessment. The physician and patient demographics were similar in the 2 treatment groups. Participants had a mean age of 61 years, 55% were women, and 16% were diabetic. Baseline BP was 154/88 mm Hg. Among those patients who were taking antihypertensive therapy at baseline, the most common agents were angiotensin‐converting enzyme (ACE) inhibitors and diuretics.

Practitioners were assigned in a 1:1 ratio to either CHEP‐based care or care based on the STITCH algorithm. The STITCH algorithm consisted of 4 steps: (1) initial therapy with a half tablet of a low‐dose ACE inhibitor/diuretic or angiotensin receptor blocker (ARB)/diuretic fixed‐dose combination (practitioners could choose from a number of commercially available products. Examples of possible initial starting dose included lisinopril‐hydrochlorothiazide (HCTZ) 10/12.5 mg daily or irbesartan‐HCTZ 150/12.5 mg daily); (2) up‐titration of initial fixed‐dose combination therapy to the highest dose available as a single tablet (examples included lisinopril‐HCTZ 20/25 mg daily or irbesartan‐HCTZ 300/25 mg daily); (3) addition of a calcium channel blocker (CCB) and up‐titration of dose (type or specific agent not specified); and (4) addition of non–first‐step antihypertensive agents, with the choice of agent at the discretion of the treating practitioner. For patients already taking antihypertensive medications at baseline, practitioners were encouraged to make subsequent additions to the therapeutic regimen in accordance with the STITCH algorithm or CHEP guidelines, respectively, but not to necessarily discontinue baseline medications. The CHEP guidelines are similar to recommendations from the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), although at the time of the study fixed‐dose combination drugs were not recommended as first‐step treatment for patients with stage 2 hypertension as they are in JNC 7 and in the subsequent 2008 CHEP recommendations. Practitioners assigned to usual care based on CHEP guidelines were not exposed to the STITCH protocol. For both treatment arms, practitioners were educated in the appropriate treatment algorithms by an implementation team consisting of the principal investigator and study personnel from the coordinating center. In addition, treatment algorithm cards (STITCH) or educational materials (CHEP) were reviewed with and provided to the enrolled practitioners. The principle investigator remained available to the family practitioners in both groups for consultation on treatment decisions. The intent was to provide equal access to expert advice and educational materials in both groups. The study staff was not blinded to treatment allocation.

The prespecified primary end point was the percentage of patients at each practice who reached goal BP (<140/90 mm Hg except in those with diabetes where the goal was <130/80 mm Hg) at 6 months of follow‐up in the STITCH group vs the CHEP group. BP was recorded based on the average of 5 readings, determined with a standardized and precalibrated automated BP device. Determination on the use of specific antihypertensive medications was based on medication logs at subject office visits. Additionally, all practitioners were given a satisfaction survey at the conclusion of the study.

After 6 months of therapy, practices randomized to STITCH were more likely to achieve adequate BP control than those randomized to CHEP (64.7% compared with 52.7%; between‐group difference 12.1%; 95% confidence interval, 1.5%–22.4%; P=.026). After adjusting for potential confounders, patients randomized to STITCH were 20% more likely to reach BP goal than those randomized to CHEP. Overall mean reduction in systolic BP was 22.6 mm Hg in practices randomized to STITCH and 17.5 mm Hg in practices randomized to CHEP (P=.002 for difference). Seven serious adverse events were recorded, 3 in the CHEP group and 4 in the STITCH group, including 3 deaths (all in the CHEP group) and 3 episodes of drug intolerance (all in the STITCH‐care group). Practitioners in the STITCH group were significantly more satisfied with their approach to managing hypertension, tended to feel that they were more effective in treating hypertension, and were more willing to recommend their approach to other physicians.

Drug logs were examined to determine the potential basis for the improved performance of practices using the STITCH algorithm. In the STITCH‐care group, 85% of patients were exposed to fixed‐dose combination therapy compared with 15% in the CHEP group (P<.001 for difference). In accordance with that finding, the number of individual drugs prescribed (with a fixed‐dose combination counting as 2 individual drugs) was significantly higher in the STITCH‐care approach compared with those assigned to CHEP care (2.3 vs 1.9 drugs, respectively; P<.001 for difference), and the proportion of patients whose antihypertensive therapy was up‐titrated during the study was higher with STITCH than with CHEP (82.6% vs 69.6%, respectively; P=.007 for difference).

In conclusion, among Canadian family physicians in solo practice, a simplified stepped‐care antihypertensive algorithm using initial low‐dose fixed‐dose combination therapy provided better BP control after 6 months than did guideline‐based care.—Feldman RD, Zou GY, Vandervoort MK, et al. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53:646–653.

Comment

Many patients with hypertension require ≥2 antihypertensive agents to control their BP, but these multi‐drug regimens are often associated with reduced therapeutic adherence. The use of simpler drug regimens, including the use of fixed‐dose combination drugs as initial therapy, might improve BP control. In this trial, use of a single‐pill, low‐dose combination ACE inhibitor/diuretic or ARB/diuretic as initial therapy was associated with better BP control after 6 months with no additional adverse effects when compared with guideline‐based care that relied on initial monotherapy. But, like many clinical trials that study “real‐world” practice‐based clinical interventions, the STITCH trial is not without a number of important limitations. Because STITCH only included Canadian family physicians in solo practices, the generalizability of these results to other practice settings in other locations, including the United States, remains unknown. All patients in STITCH had access to a primary care physician and were able to receive affordable antihypertensive medications through the Canadian health care system. As such, this study does not address overcoming barriers to community‐wide BP control more common in the United States, including problems with access to medical care and the affordability of antihypertensive medications. In addition, there appears to be a selection bias among the participating practices and perhaps even among participating patients. Since only about half of the practices originally randomized completed the clinical trial, use of an intention‐to‐treat principle would have led to far less impressive results. This indicates a potential difficulty in instituting widespread change in community‐based primary care practices. Additionally, while the protocol called for enrollment of consecutive patients seen at each physicians’ office, it is possible that physicians may have chosen not to enroll some of their more difficult patients or those patients may have chosen not to participate. Finally, the short 6‐month study duration may have biased the study against the CHEP group, which may have required more titration steps in order to get to goal BP. Whether the difference in BP control found at 6 months could be sustained over time is an important and clinically relevant question that could potentially be answered by long‐term follow‐up of STITCH study participants.

Despite these concerns, STITCH teaches us that important barriers to BP control may be overcome by relatively simple interventions. It appears that clinical or therapeutic inertia, the failure to increase the intensity of therapy despite the presence of poorly controlled BP control, can be overcome by using an algorithm beginning with fixed‐dose combination therapy in a single pill. As evidenced in STITCH, individual clinicians using a stepped‐care guideline approach (CHEP) can control more than half (53%) of their uncomplicated and uncontrolled hypertensive patients starting with monotherapy, but achieve even better results (65%) by using a simplified treatment algorithm based on initial fixed‐dose combination therapy. Of note, primary care clinicians randomized to the STITCH algorithm were more likely to recommend this approach to other clinicians, suggesting that they were more satisfied and comfortable with this different approach. Importantly, in our cost‐constrained environment, all 4 steps in the STITCH algorithm can be accomplished with the use of generic medications, including an ACE inhibitor (although ARBs were used in some patients), thiazide‐type diuretic, CCB, and additional agents as needed.

The present results are complementary to recently published data from the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. ¹ ACCOMPLISH was a prospective, randomized, clinical trial that compared the effect of initial fixed‐dose combination therapy with an ACE inhibitor/diuretic compared with ACE inhibitor/CCB therapy (with other classes of medications added as needed to get BP effectively controlled) on the incidence of subsequent cardiovascular events. The majority of patients enrolled in ACCOMPLISH were taking antihypertensive medications at baseline, yet only 37% were controlled. After changing to study medication, use of these fixed‐dose combinations as initial therapy led to a 73% control rate 6 months into the study.

These data suggest that a simplified algorithm for the treatment of uncomplicated hypertension using initial low‐dose combination antihypertensive therapy with prespecified up‐titration steps can more favorably and quickly control BP without an increase in adverse effects. Unlike in clinical practice, where access to the clinician remains a substantial barrier to care, in clinical trials, BP medication algorithms are usually implemented by a study coordinator and/or clinical pharmacist. Physicians generally determine whether a patient is appropriate for treatment with the study algorithm (enrollment) and are further consulted when patients have adverse events with study medications, have a need to deviate from the protocol (algorithm), or have suboptimal BP control. Even when patients are seen by their physician, in a busy, time‐constrained clinical practice, acute medical issues may take precedence over up‐titration of BP medications (often termed tyranny of the urgent). While there are a number of important differences between care delivered in clinical trials and in clinical practice (including patient motivation, amount of individualized counseling, duration of face‐to‐face time with staff, and access to medications), relying on access to physicians or other practitioners with prescribing privileges may not be the most effective means of improving BP control rates. Use of treatment algorithms, like the one used in STITCH, implemented by other clinical staff such as nurses or clinical pharmacists, may overcome significant barriers to better BP control. In theory, physicians would determine suitability for a patient to enroll in such a given algorithm or protocol and would be further consulted if side effects to medications were identified or if BP remained uncontrolled after several titration steps. Similar strategies may also be applicable for treatment of other cardiovascular risk factors such as lipid and glycemic control. While such an approach would require a major restructuring of our current health care delivery system, this approach has already been implemented in Veterans Administration hospitals using clinical pharmacists.

Until we change our process for delivering health care, simplified stepped‐care algorithms like the one used in STITCH can and should be adopted by primary care clinicians in their individual practices. In additional, future guidelines must emphasize the importance of initial fixed‐dose combination therapy in the treatment of hypertension. While JNC 7 recommends initial combination therapy for patients with stage 2 hypertension (or when BP is at least 20/10 mm Hg above goal), ² this option might potentially be extended to include all patients with hypertension, regardless of their initial BP levels. Let’s keep it simple. Given our current armamentarium of BP medications and persistently low control rates, why shouldn’t one size fit all, or at least most.