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Low-dose, triple combination therapy effective in mild to moderate hypertension
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Patients with mild to moderate hypertension who were treated with a pill that contained low doses of three antihypertensive drugs were more likely to achieve target BP goals compared with those who received usual care, according to a study published in JAMA.
Hypertension in Sri Lanka
Ruth Webster, PhD, head of research programs at The George Institute for Global Health in Camperdown, Australia, and senior lecturer at University of New South Wales, and colleagues analyzed data from 700 patients (mean age, 56 years; 58% women; mean baseline BP, 154/90 mm Hg) with persistent hypertension that either required initiation of pharmacological treatment or titration of pharmacological treatment from 11 urban hospital outpatient departments in Sri Lanka. Patients were excluded if they were currently using two or more BP-lowering drugs, had accelerated hypertension, severe or uncontrolled BP, an unstable medical condition or a contraindication to any components of the therapy to be used in the study.
Patients were randomly assigned triple combination pill therapy (n = 349) or usual care (n = 351). Triple combination therapy consisted of 2.5 mg amlodipine, 20 mg telmisartan and 12.5 mg chlorthalidone, which was to be taken once daily. The treating physician could decide during follow-up whether the therapy should be maintained, discontinued or uptitrated. The higher-dose version of the triple combination therapy contained 5 mg amlodipine, 40 mg telmisartan and 25 mg chlorthalidone.
Patients attended study visits at registration, randomization, 6 weeks, 12 weeks and 6 months.
The primary outcome of interest was the proportion of patients who achieved target BP at 6 months, defined as BP less than 140/90 mm Hg. Secondary outcomes of interest included proportion of patients who achieved target BP at 6 and 12 weeks, adherence at 6 months, systolic and diastolic BP changes at 6 months and intolerance to the treatment at 6 months.
Nearly all patients completed the trial (96%).
At 6 months, BP targets were achieved by 69.5% of patients assigned triple combination pill therapy vs. 55.3% assigned usual care (adjusted RR = 1.23; 95% CI, 1.09-1.39; risk difference = 12.7%; 95% CI, 3.2-22). The triple combination pill therapy group had a mean BP of 125/76 mm Hg at 6 months compared with 134/81 mm Hg in the usual-care group. The adjusted difference in post-randomization BP was –9.8 mm Hg for mean systolic BP (95% CI, –7.9 to –11.6) and –5 mm Hg for mean diastolic BP (95% CI, –3.9 to –6.1).
Adverse events
During the study, 419 adverse events occurred, with 38.1% of patients from the triple combination pill therapy group reporting at least one event vs. 34.8% of patients from the usual-care group. Common adverse events for the triple combination pill therapy group and usual-care group included dizziness, musculoskeletal pain (6% vs. 8%, respectively), presyncope or syncope (5.2% vs. 2.8%, respectively).
The number of patients that withdrew from BP-lowering therapy because of adverse events was not different in the triple combination pill and usual-care groups (6.6% vs. 6.8%, respectively).
“The results are also particularly important in light of recent recommendations for lower blood pressure targets in high-risk individuals,” Webster and colleagues wrote. “In the United States, one of the most effective implementation programs for blood pressure control involved organized systems of regular prescription review, with a large component focused on more extensive use of combination therapy at earlier stages within treatment protocols. The results of this study strongly reinforce use of a combination therapy approach.”
In a related editorial, Mark D. Huffman, MD, MPH, associate professor of preventive medicine (epidemiology) and medicine (cardiology) at Northwestern University Feinberg School of Medicine, and colleagues wrote: “Efficiency gains from fixed-dose combination therapy will likely be greater in settings in which barriers are more prevalent than in the United States and these barriers include complex drug supply chain, limited access to medications and shortage of health care workers to titrate medications. The global scale of elevated BP suggests that an intervention like a fixed-dose combination, which appears to be effective, safe and efficient, is more likely to be sustained than more complex, labor-intensive approaches.” – by Darlene Dobkowski
Disclosures: Webster reports she received a salary from George Health Enterprises. Huffman reports he received funding from the World Heart Federation when serving as a senior program adviser for the emerging leaders program, which received funding from Boehringer Ingelheim and Novartis and previous support from AstraZeneca and Bupa. Please see the study and editorial for all other authors’ relevant financial disclosures.
Perspective
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Keith C. Ferdinand, MD
The study appears to be well done, and it confirms what we actually had suggested as early as JNC 6 in 1998: In patients especially with BP greater than 20 mm Hg systolic over 10 mm Hg diastolic above goal, the use of single-pill combinations may actually increase BP control.
The reason for that has always been a combination of factors. One is that less pill burden may increase adherence, although adherence was not documented to be different in this particular study. That may have been due to the fact that when people participate in clinical trials, they tend to adhere more than free-living individuals.
The other reason the combination pills may be beneficial is that there is less need for titrations, add-ons and switches. Frequent medication changes can confuse patients and lead to less adequate BP control.
There are many factors that come into play but, in this particular trial, the researchers were able to show using three drugs, at what they considered lower doses, may have actually been beneficial.
There are several indications that this paper may benefit patients in the United States and developed societies. One is the drug that they used in the so-called low dose was 12.5 mg of chlorthalidone. We know that chlorthalidone on a milligram-to-milligram basis is more effective for BP reduction than hydrochlorothiazide. That 12.5 mg of chlorthalidone actually may reflect more 25 mg of hydrochlorothiazide, which is consistently used as the dose in the United States.
Also, 2.5 mg of amlodipine, although it is relatively low dose, often may be effective for BP reduction. In this particular trial, adding the angiotensin receptor blocker to the calcium-channel blocker would benefit the patients for BP reductions. While it is considered “low dose,” it is an adequate dose as a starting dose of chlorthalidone, perhaps an effective dose of amlodipine and telmisartan, which combined gave a benefit.
The study was done in Sri Lanka. According to the report, the prevalence of hypertension in Sri Lanka is about 24%, which is much lower than what we see in the United States. Nevertheless, this can be considered reflective of the type of patients we would see in the United States because 33% were overweight and 18% were obese (BMI greater than 30 kg/m2) The average LDL was 123.9 mg/dL, 29% had diabetes and the mean BP of 154 mm Hg systolic over 90 mm Hg diastolic.
Changes in electrolytes and LDL seen with chlorthalidone may not be as important for CV outcomes as the lowering of BP, as documented within the ALLHAT trial (The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;doi:10.1001/jama.288.23.2981), there did seem to be a small increase in cholesterol and glucose, but the chlorthalidone first step in high-risk patients in ALLHAT had better outcomes. Physicians should not be dismayed if they see some modulation in electrolytes and LDL.
Adherence and the lack of withdrawals being the same with combination and usual care is comforting. However, remember within clinical trials, patients appear to have better adherence and tolerate therapies more than they do in free-living populations. Physicians who embrace combination therapy should be aware that if patients have dizziness or other side effects, this regimen may be less than an appropriate way of treating their BP.
Based on these findings, in conventional clinical practice, it is reasonable to start with combination therapy. Whether three drugs will be a standard going forward would have to probably be tested more rigorously in the U.S. population.
Clearly, the Kaiser Permanente Northern California experience (Jaffe MG, et al. JAMA. 2013;doi:10.1001/jama.2013.108769), which was reported in this particular paper in a U.S. cohort, showed that starting with combination therapy may actually increase BP control. Within the Kaiser Permanente system, they start with a combination of lisinopril and hydrochlorothiazide, but combinations of drugs including amlodipine and an angiotensin system agent has been shown to be beneficial, not only for BP but perhaps also outcomes, as shown in the ACCOMPLISH trial (Jamerson K, et al. N Engl J Med. 2008;doi:10.1056/NEJMoa0806182), which used benazepril and amlodipine.
While further study may be beneficial in the U.S., this trial offers more confirmatory evidence that combination therapy is beneficial in middle-aged patients who have significant hypertension and high-risk status including a significant proportion with diabetes. Clinicians, especially for persons who have BP 20 mm Hg systolic over 10 mm Hg diastolic greater than seen at baseline and for those patients who have high risk, including age, diabetes and elevated LDL, may consider combination therapy an appropriate first step.
In the guidelines recently published by the American College of Cardiology, American Heart Association and other major medical societies (Whelton PK, et al. J Am Coll Cardiol. 2017;doi:10.1016/j.jacc.2017.11.006), in their final recommendations of strategies to improve hypertension treatment and control, they suggest adherence strategies including once-daily dosing and combination pills. They also suggest team-based care.
Simplifying therapy, providing patients the ability to have their BP evaluated out of office at home and with other BP team member managements including physician assistants and nurse practitioners will increase BP control across this population, compared with waiting for the conventional physician’s visit and doing stepped-up monotherapy and sequential changes in BP, which confounds the care and often increases the cost of care. Based on this research, the Kaiser Permanente experience and other clinical trials, it is not only not as effective, but perhaps will give the least effective means of controlling BP than starting with combinations.
The 2018 European Society of Cardiology and European Society of Hypertension guidelines for treatment of hypertension (Williams B, et al. Eur Heart J. 2018;doi:10.1093/eurheartj/ehy339) were presented in August at the ESC Congress. The new ESC/ESH guidelines recommend starting with a two-drug combination in most patients as initial therapy vs. a stepwise treatment. Also, the European hypertension report notes that nonadherence plays a major role in poor control of BP and increases with greater number of pills. Therefore, the authors suggest that two-drug or even three-drug combination in a single tablet could transform BP control rates.
While it is suggested to be low-dose combination therapy, effective combination therapy would probably be a better description of this particular regimen.
Tulane University School of Medicine
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