Polypills Show Promise in Diverse Hypertensive Patient Groups

Polypills formulated to combine three or four antihypertensive medications may be effective treatment strategies for a variety of patient types, three new studies presented at the European Society of Cardiology Congress 2024 suggest.

For two of the studies, investigators tested a low-dose triple polypill combination in a RCT and then in a dose-comparison trial against three dual therapies to assess the efficacy of each component of the polypill. BP was reduced in mild-to-moderate hypertension and was more effective than dual therapy in a diverse patient population, with the investigators suggesting that the polypill may help overcome therapeutic inertia.

In the third study, patients with resistant hypertension responded better to a four-drug polypill than to one that contained a combination of three drugs.

“With low doses, you keep most of the efficacy, but you lose most of the side effects from the basic clinical pharmacology, and with a single pill, hopefully you keep the patient adherence maximized,” said Anthony Rodgers, PhD (The George Institute for Global Health, University of New South Wales, Sydney, Australia), in a press conference prior to his presentation.

Polypills for hypertension are not a new idea, with a recent meta-analysis showing that for the initial treatment of hypertension, combination pills containing low doses of three or four antihypertensive agents are better at lowering blood pressure than monotherapy, usual care, or placebo and are generally well tolerated. Other individual trials, including QUARTET and TRIUMPH, also have shown promise for this strategy.

GMRx2 Studies Show Rapid Control

Rodgers and colleagues tested GMRx2 (George Medicines), a polypill that contains telmisartan, amlodipine and indapamide in three dose strengths: triple quarter doses (10 mg, 1.25 mg, and 0.625 mg, respectively), triple half doses (20 mg, 2.5 mg, and 1.25 mg) and triple standard doses (40 mg, 5 mg, and 2.5 mg).

In the international RCT, 295 patients who were on zero to three antihypertensive medications at baseline had a 2-week placebo run-in period during which medications were stopped. The mean BP measured in clinic was 138/86 mm Hg. Individuals with a systolic BP on home measurement of 130-154 mm Hg were randomized to the triple quarter dose, triple half dose, or placebo.

At 6 weeks, 70% of patients in the triple half-dose group, 65% in the triple quarter-dose group, and 37% in the placebo group achieved a BP of < 140/90 mm Hg as measured in clinic (P < 0.0001 for all comparisons). Treatment withdrawal due to adverse events occurred in 5.1% in the half-dose group, none of the quarter-dose group, and 1.6% of the placebo group.

With low doses, you keep most of the efficacy, but you lose most of the side effects from the basic clinical pharmacology, and with a single pill, hopefully you keep the patient adherence maximized. Anthony Rogers

The larger efficacy trial looking at individual dose components enrolled 1,385 adults from Australia, Czech Republic, New Zealand, Poland, Sri Lanka, the United Kingdom, and the United States.

All patients were receiving zero to three BP-lowering drugs at baseline, with a baseline rate of BP control (< 140/90 mm Hg) of 35%.

All patients received the triple half dose polypill for 4 weeks and then were randomized to continue the triple half dose or dual combination at half doses: (telmisartan 20 mg/amlodipine 2.5 mg, telmisartan 20

mg/indapamide 1.25 mg, or amlodipine 2.5 mg/indapamide 1.25 mg). Barring contraindications, all groups had their doses doubled at week 6. The primary efficacy outcome was mean change in home systolic BP from baseline to week 12.

Overall, the triple therapy was superior to all dual combinations, with a 74% rate of BP control compared with a rate of 61% for both the amlodipine-indapamide and the telmisartan-indapamide group, and just 54% in the telmisartan-amlodipine group (P < 0.0001 for all comparisons).

“We'd suggest this is hopefully a new therapeutic option for hypertension [including] initial treatment in those uncontrolled on monotherapy and hopefully part of an important advance for what is our leading cause of cardiovascular disease,” Rodgers noted in the press conference.

To TCTMD, he said although the individual fixed doses of the polypills prevent titration of individual components if patients experience side effects, “the strategy with this drug is it does have three dose versions, and so the idea would be to move down to one of the less potent [versions].”

QUADRO

For the QUADRO polypill trial, Stefano Taddei, MD (University of Pisa, Italy), and colleagues first enrolled patients with resistant hypertension to an 8-week run-in period where they received a triple polypill containing perindopril, indapamide, and amlodipine (10/2.5/5 mg or 10/2.5/10 mg daily, if tolerated).

Despite adherence to therapy, 183 patients (mean age 57 years; 47% female) remained uncontrolled after the 8 weeks. They were then randomized to either continue the triple therapy they were taking or to receive a quadruple polypill containing perindopril, indapamide, amlodipine, and bisoprolol (10/2.5/5/5 mg or 10/2.5/10/5 mg daily). Mean office BP at baseline was 150.3 mm Hg/90 mm Hg.

At 8 weeks, the primary endpoint of change in office systolic BP was greatest in the quadruple pill group, with a reduction of 20.67 mm Hg versus a reduction of 11.32 mm Hg in the triple pill group. Similarly, for the main secondary endpoint of change in mean ambulatory systolic BP, the difference was greater in the quadruple pill group, with a reduction of 14.09 mm Hg versus 6.97 mm Hg (P < 0.0001 for both comparisons).

BP control, defined as office sitting BP < 140/90 mm Hg, was achieved in 66.3% of patients on the quadruple pill versus 42.7% of those on triple therapy (P = 0.001). Ambulatory BP normalization, defined as mean BP over 24 hours of < 130/80 mm Hg was achieved in 51.2% of those in the quadruple pill group and 20.7% in the triple pill group (P < 0.0001). Additionally, home BP normalization, defined as < 135/85 mm Hg was achieved in 60.7% versus 25.4%, respectively (P < 0.0001).

Resistant hypertension, while leading to an increased cardiovascular risk, is difficult to treat, demanding a number of pills with not enough safe and practical options. Stefano Taddei

“The key message is that resistant hypertension, while leading to an increased cardiovascular risk, is difficult to treat, demanding a number of pills with not enough safe and practical options,” Taddei said in the press conference. “The possibility to use four well-established drugs in a single pill combination may improve adherence.”

He added that one of the advantages of the quadruple pill used in QUADRO is that the individual drugs comprising it are relatively cheap, which could make it particularly useful in developing countries to manage patients with resistant hypertension and/or antihypertensive compliance issues.

To TCTMD, he said that allowing patients to cut back on the overall number of pills they need to take to manage their CVD is another positive aspect of the quadruple pill.

“Fifty percent of patients with chronic disease [such as] hypertension, hypercholesterolemia, diabetes, don't take their drugs. So this is the best way that we can improve drug adherence for our patients,” Taddei added.