The American Journal of Medicine
Volume 122, Issue 3 , Pages 290-300, March 2009

Combination Therapy Versus Monotherapy in Reducing Blood Pressure: Meta-analysis on 11,000 Participants from 42 Trials

Wolfson Institute of Preventive Medicine at Barts and The London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom

Article Outline

Abstract 

Objective

To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose.

Methods

Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo.

Results

We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]).

Conclusion

Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.

Keywords: Angiotensin-converting enzyme inhibitor, Beta-blocker, Blood pressure, Calcium channel blocker, Combination blood pressure therapy, Randomized trial, Thiazide

 

Monotherapy is the standard initial treatment for reducing blood pressure in most patients with hypertension, moving to combination therapy (2 or more drugs from different classes) when stepwise increases in the dose of 1 drug fail to achieve the desired decrease in blood pressure.1, 2, 3, 4 A meta-analysis published in 2003 showed that halving the dose of most blood pressure-lowering drugs substantially reduced the prevalence of adverse effects but reduced the blood pressure-lowering effect by only approximately 20%,5 supporting proposals for the use of low-dose drug combinations as the first-line treatment for the control of blood pressure.5, 6, 7, 8

Clinical Significance

 


•Monotherapy is the standard initial treatment for reducing blood pressure, with stepwise increases in dose if the desired decrease in blood pressure is not achieved.

•Combining drugs from different classes is approximately 5 times more effective in lowering blood pressure than increasing the dose of 1 drug.

•Combination therapy is the preferred initial strategy in the treatment of high blood pressure.

The effectiveness of this approach relies on there being additive effects between the different classes of drugs when used together, such that the combined blood pressure-lowering effect of 2 together is the sum of each alone. Randomized trials of factorial design are required to quantify the effect of giving 2 drugs together, using 4 groups with 1 drug alone, the other drug alone, both drugs together, and placebo. Such trials have been published on each of the 4 most widely used classes of drugs (thiazides, beta-blockers, angiotensin-converting enzyme [ACE] inhibitors, and calcium channel blockers).9 We examine the evidence for additive effects of all pairwise combinations on a class-specific basis. For each of the 4 classes of drug we sought to quantify the incremental blood pressure-lowering effect of using any 1 class of drug in combination with another class and to assess the efficacy of combinations compared with using 1 drug in double dose.

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Materials and Methods 

Randomized trials using a factorial design were identified using a search of Medline, Cochrane Collaboration, and EMBASE databases in English from 1966 to March 2008. We used generic and trade names of all drugs in the 4 classes, thiazide, beta-blocker, ACE inhibitor, and calcium channel blocker taken from reference pharmacopoeias as key or text words and combined them in pairs. The resulting citations were limited to those of Medline publication type “clinical trial” or “randomized-controlled trial.” We excluded trials under 2 weeks duration, with no placebo group or with a nonrandomized order of treatment and placebo. These exclusions apart, we included all randomized placebo-controlled trials comparing any drugs of 2 of the 4 main classes specified above. The initial search identified 1697 articles, which was reduced to 778 after screening the title, to 92 after inspection of the abstracts, and to 4210, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 after examining the full articles, including a hand search of citations in the reports of published trials and systematic reviews. We also undertook a search of Food and Drug Administration and Industry websites but identified no additional trials that met the inclusion criteria. Data were abstracted independently by 2 investigators, and any inconsistencies were resolved by discussion and referral back to the original articles.

Statistical Analysis 

We calculated the mean blood pressure reductions in each trial as the reduction in the treated group minus that in the placebo group or, in crossover trials, end-treatment minus end-placebo blood pressure (with its standard error) for each drug taken separately and for both drugs taken together. For each of the 4 classes of drug in turn, we used a random effects model to estimate the average placebo-adjusted blood pressure reduction from the specified class of drug, the average reduction from the comparison drugs, and the 2 drugs together. For example, in all randomized trials that considered pairwise comparisons of thiazides and another class of drug, we calculated the mean placebo-adjusted reduction in blood pressure on thiazides alone, on the comparison drugs alone, and on both drugs together. We specified equivalent doses of different drugs by identifying the usual maintenance dose of each drug as recommended in reference pharmacopoeias.5, 52 We referred to this as the “standard dose” and expressed the dose of each drug in each trial as a multiple of the standard dose. Meta-regression analyses of blood pressure reduction on the standardized doses of the drugs were used to investigate possible sources of heterogeneity. STATA software was used (StataCorp, College Station, Tex).

For each class of drug the observed blood pressure reduction on the combination was compared with the expected blood pressure reduction based on the effect of both drugs together being additive. Because the blood pressure-lowering effect of a given dose of drug depends on pretreatment blood pressure, the expected blood pressure reduction from 2 drugs was the sum of each drug alone allowing for the smaller reduction from an added drug because of the decreased blood pressure from the initial drug.52 For example, if 2 drugs, A and B, lower systolic blood pressure by a mm Hg and b mm Hg, respectively, from a given pretreatment blood pressure (z mm Hg) when used alone, the expected effect of both together is less than (a+b) mm Hg because drug B effectively operates from a pretreatment blood pressure that is a mm Hg lower than z mm Hg, as a result of drug A. A previous meta-analysis5 showed that the blood pressure-lowering effect of a drug is approximately 1 mm Hg less for each 10 mm Hg decrement in pretreatment blood pressure. So, the expected blood pressure reduction due to A plus B, is (a+b−a×0.1) mm Hg, taking A as the initial drug and (b+a−b×0.1) mm Hg, taking B as the initial drug; the average is a+b − 0.1×(a+b)/2 or 0.95 (a+b) mm Hg. The expected effect of 2 classes of drug taken together is therefore 95% of the sum of the blood pressure reductions for each class of drug taken alone.

We also calculated the observed incremental blood pressure reduction from 2 classes of drug together relative to 1 drug alone and divided this by the expected incremental effect, to give a ratio of observed to expected incremental effects. For each trial, the observed incremental blood pressure reductions from 2 classes of drug together (A and B) compared with the reduction from 1 alone was calculated by subtracting the average blood pressure reduction for each drug alone 0.5 (a+b) mm Hg from the reduction due to the combination of 2 drugs. The expected incremental blood pressure reduction from 2 classes of drug compared with 1 alone was the expected blood pressure reduction due to the combination (0.95 (a+b) mm Hg, as derived above) minus the average effect of each drug alone 0.5 (a+b) mm Hg. The ratios of observed to expected incremental effects had a log Gaussian distribution, so a weighted geometric mean was calculated for each class of drug by weighting the ratios for each trial by the number of participants allocated to each treatment in each study.

We compared the ratio of observed to expected incremental blood pressure reductions with the equivalent effects of doubling the dose of each class of drug by using the results of a previous meta-analysis that examined the blood pressure-lowering effects of different classes of drugs at fixed dose.5 For each of the 4 classes of drug, the observed incremental effect of doubling dose was calculated by subtracting the blood pressure reduction at twice the standard dose from that at the standard dose.5 The expected effect of doubling dose (eg, of drug A), assuming an additive effect, was double the blood pressure reduction from using the drug at standard dose (a mm Hg), allowing for the effect of the lower pretreatment blood pressure, as described above (ie, 0.95×2a mm Hg). The expected incremental effect was therefore 0.95×2a – a, or 0.9a mm Hg. For each of the 4 classes of drug, the ratio of the observed to the expected incremental effect was calculated and compared with the incremental effects of combining each class of drug with any other class.

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Results 

Table 1 shows details of the 42 randomized factorial trials included, involving 101 comparisons between pairs of drugs (some trials compared 2 drugs in different doses) and 10,698 participants (10,333 in parallel group design trials and 365 in crossover trials). All but 1 trial (conducted in general practice) recruited patients attending hospital outpatient hypertension clinics, generally without a history of coronary heart disease, stroke, diabetes, or renal disease. In the individual trials, the duration ranged between 4 and 12 weeks, mean age was between 46 and 71 years, and pretreatment blood pressure was between 136 and 173 mm Hg systolic and 84 and 110 mm Hg diastolic.

Table 1. Details of the 42 Trials Included in the Meta-analysis

*ACE-I = ACE inhibitor; BB = beta blocker; CCB = calcium-channel blocker;

⁎⁎HCTZ = hydrochlorothiazid.

Figure 1 shows the mean (and 95% confidence intervals) placebo-subtracted systolic blood pressure reductions observed in the trials for each of the 4 drug classes alone, for the comparison drug alone (from any of the other 3 classes), and for 2 drugs together. The expected blood pressure reduction from both drugs together (assuming an additive interaction) is shown by the upper dotted line in Figure 1 for each of the 4 drug classes. The observed and expected effects of both drugs together are close, showing that the average effect of combining each class of drug with a drug from another class is approximately additive.

  • View full-size image.
  • Figure 1. 

    Mean placebo-subtracted systolic blood pressure reduction from a meta-analysis of 42 randomized factorial trials of thiazides, beta-blockers, ACE inhibitors, or calcium channel blockers using each class of drug separately, any 1 of the other 3 classes alone, and in combination with the specified drug class (95% confidence interval). The dashed line represents the expected blood pressure reduction from the combination assuming an additive effect, allowing for the smaller reduction from 1 drug given the lower pretreatment blood pressure because of the other. BP=blood pressure; ACE=angiotensin-converting enzyme.

Figure 2 shows, for each of the 4 classes of drug combined with any other, the ratio of observed to expected incremental systolic blood pressure-lowering effects of 2 drugs compared with 1 drug alone. For each class of drug the effect of adding a second drug was close to that expected, that is, a ratio of 1.0. The estimates for each combination were thiazide plus any other class 1.04 (0.88-1.20), beta-blocker plus any other class 1.0 (0.76-1.24), ACE inhibitor plus any other class 1.16 (0.93-1.39), and calcium channel blocker plus any other class 0.89 (0.69-1.09). The average across all classes was 1.01 (0.90-1.12). Using 1 drug in double dose achieved ratios, respectively, of 0.19 (0.08-0.30), 0.23 (0.12-0.34), 0.20 (0.14-0.26), and 0.37 (0.29-0.45) for thiazides, beta-blockers, ACE inhibitors, and calcium channel blockers, respectively, an average of 0.22 (0.19-0.25). In every instance, combination therapy was more effective than increasing the dose of 1 drug, and this was statistically significant (P<.05) for all comparisons.

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  • Figure 2. 

    Ratio of observed to expected incremental blood pressure-lowering effects of adding a drug or doubling the dose according to the class of drug. The expected incremental effect is the incremental blood pressure reduction of the added (or doubled drug), assuming an additive effect and allowing for the smaller reduction from 1 drug (or dose of 1 drug) given the lower pretreatment blood pressure because of the other. ACE=angiotensin-converting enzyme.

The mean doses of the drugs in the trials were close to the standard (or usual maintenance) dose,52 ranging between 0.5 and 1.6 multiples of standard. There was evidence of heterogeneity of blood pressure-lowering effects across the individual trials of thiazides (P<.01), beta-blockers (P=.06), ACE inhibitors (P=.08), and calcium channel blockers (P<.01), which was largely explained by the different doses of drugs used in the trials. A meta-regression analysis of blood pressure reduction on dose (with all trials of a given class of drug stratified according to the dose used) showed that the heterogeneity was no longer present (P>.05 for all classes of drug).

Figure 3 shows, for each of the 4 classes of drug, a plot of the observed placebo-subtracted blood pressure reduction for that class of drug combined with any other drug compared with that expected, assuming an additive interaction and allowing for the blood pressure reduction due to the initial drug. Each circle represents a different 2-drug combination at the doses used. The area of the circle reflects the statistical precision of the points plotted. For each class of drug, the circles are on or close to the line of identity (where observed equals expected), revealing a consistent effect across all studies and across doses of drug within trials.

  • View full-size image.
  • Figure 3. 

    Comparison of observed placebo-subtracted reduction in systolic blood pressure of 2 drugs together against the expected effect of 2 drugs together according to the class of drug in factorial trials of 2 blood pressure-lowering drugs (the expected effect assumes a full additive effect and allows for the smaller reduction from 1 drug given the lower pretreatment blood pressure because of the other). Each circle represents a different drug and dose combination within a trial. There are more circles than trials because several trials examine different doses of different drugs. The area of the circle reflects the statistical precision of the points plotted. The diagonal lines are the lines of identity where observed equals expected. ACE=angiotensin-converting enzyme.

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Discussion 

The results from this meta-analysis show that for each of the 4 classes of blood pressure-lowering drug considered, the blood pressure reduction from each class of drug combined with 1 from another class is approximately additive. The additional effect of combining given doses of 2 classes of drug is approximately 5 times more effective than doubling the dose of 1 drug.

The incremental effect of an additional drug was expressed as the ratio of the observed to expected extra blood pressure reduction. The latter is the sum of the reductions from each drug allowing for the reduced effect of the added drug due to the lower blood pressure achieved by the existing drug. This is needed to take account of a drug at a given dose having a smaller blood pressure-lowering effect in a person with a lower blood pressure than in a person with a higher blood pressure.52 An incremental effect of 1.0 thus indicates that the effect is exactly additive, 0.5 indicates a subadditive effect (equivalent to 50% of the extra additive effect), and 1.5 indicates a supra-additive (or synergistic) effect (equivalent to 50% greater than additive). Overall, our result of 1.01 (the average of the summary estimates from each class of drug) is close to the effect being exactly additive.

This analysis combined data from trials of all possible pairwise combinations of the 4 most widely used classes of blood pressure-lowering drugs, allowing the additive effects of each class of drug to be quantified on a class-specific basis. Angiotensin-II receptor blockers were not included in the meta-analysis because being a newer class of drug, there are few factorial trials and they do not encompass all the pairwise comparisons. Nonetheless, 3 published trials showed additive effects in combination with thiazides53, 54, 55 and 1 published trial showed additive effects in combination with calcium channel blockers.56

“Monotherapy” and “stepped-care” is the usual initial approach to treating blood pressure in most patients with hypertension, in which a trial of treatment is started in each patient, increasing the dose of 1 drug before adding others if specified blood pressure “targets” are not reached. The British BHS 2004 and NICE/BHS 2006 clinical practice guidelines recommend this as the initial approach in all patients.1, 2 The American Joint National Committee VII3 and the European Society of Cardiology/European Society of Hypertension 20074 guidelines also advocate this as the general approach, but recommend using 2 drugs initially if a person's blood pressure is particularly high (≥160 mm Hg systolic or ≥90 mm Hg diastolic) and in patients with specific indications (eg, diabetes or a myocardial infarction). Although the value of routinely starting treatment with combination therapy, particularly with low doses, has been proposed,5, 6, 7, 8 this has not been widely accepted. No guideline recommends combination rather than monotherapy as a matter of routine in all patients. The substantial advantage of this approach, over increasing dose, is clear from the results presented here, based on many studies, across different doses and pretreatment blood pressure levels. The results leave little doubt over the advantages of adopting low-dose combination blood pressure-lowering treatment as routine initial therapy for all, instead of a monotherapy and stepped-care approach.

A single blood pressure-lowering drug at standard dose reduces diastolic blood pressure by approximately 5 mm Hg,5 equivalent to approximately a 25% reduction in risk of coronary heart disease events (relative risk 0.75) and approximately a 35% reduction in stroke (relative risk 0.65), at age 65 years, from a meta-analysis of 61 cohort studies supported by a meta-analysis of 147 randomized trials.57, 58 Our results indicate that doubling the dose of a single drug would increase the blood pressure reduction from approximately 5 to 6 mm Hg, which would reduce coronary heart disease events by 29% (because 0.756/5=0.71), an additional 4 percentage points, and reduce stroke by 40% (0.656/5 = 0.60), an additional 5 percentage points. Combining 2 drugs from different classes would increase the blood pressure reduction from approximately 5 to 9 mm Hg, which would reduce coronary heart disease events by 40% (0.759/5=0.56), an additional 15 percentage points, and reduce stroke by 54% (0.659/5 = 0.46), an additional 19 percentage points. This means that for every 1 incremental coronary heart disease event or stroke prevented by doubling the dose of a single drug, 4 events would be prevented by using combination therapy.

Low-dose therapy has the advantage of reducing adverse effects that, with the exception of ACE inhibitors and angiotensin receptor blockers, are strongly dose related; for 2 classes (thiazides and calcium channel blockers), for example, adverse effects are 80% lower at half-standard than standard dose.5 The prevalence of adverse effects from combining 2 drugs at half-standard dose would therefore, for most combinations, be lower than with 1 drug at standard dose. Using more than 2 drugs in combination also would increase efficacy; 3 drugs at half-standard dose (compared with 2 at standard dose) would, for example, reduce diastolic blood pressure by approximately another 2 mm Hg (from 9 to 11 mm Hg) with expected reductions in the risk of coronary heart disease and stroke of 46% and 63%, respectively. The use of combination low-dose therapy therefore has greater efficacy and less toxicity than using a higher dose of a single drug.

There may be concerns that such an approach may lower blood pressure below the so-called blood pressure “targets” often regarded as optimal.1, 2 The evidence, however, is against the view that there is some target blood pressure level within the range of values in Western populations below which further blood pressure reduction has no further effect in preventing cardiovascular disease. Epidemiologic studies show a continuous proportionate reduction in risk of heart disease and stroke with decreasing blood pressure, without threshold.57 Over time, patients entered into trials of blood pressure reduction have been selected with lower and lower blood pressures and the trials have shown no attenuation of the relative reduction in disease events,59, 60, 61, 62, 63 as expected from the epidemiologic studies.5 Setting blood pressure targets needlessly limits the potential for preventing heart attacks and strokes through blood pressure reduction.

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Conclusions 

Combining blood pressure-lowering drugs from different classes is approximately 5 times more effective than doubling the dose of 1 drug. It follows that to maximize efficacy combination therapy, preferably using low doses to minimize side effects, is substantially better than monotherapy and should be considered as routine initial therapy.

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Acknowledgments 

We thank Andrew Archbold, Jan Mackie, and Mark Caulfield for comments on drafts of this article.

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References 

  1. Williams B, Poulter NR, Brown MJ, et al. Guidelines for the management of hypertension: report of the fourth working party of the British Hypertension Society, 2004 – BHSIV. J Hum Hypertens. 2004;18:139–185
  2. CG18 Hypertension (persistently high blood pressure) in adults—NICE guideline. Available at: www.nice.org.uk.
  3. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (The JNC 7 Report). JAMA. 2003;289:2560–2573
  4. The Taskforce for the management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Guidelines for the Management of Arterial Hypertension. J Hypertens. 2007;25:1105–1187
  5. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427–1434
  6. Frishman WH, Bryzinski BS, Coulson LR, et al. A multifactorial trial design to assess combination therapy in hypertension. Arch Intern Med. 1994;154:1461–1468
  7. Moser M, Prisant LM. Low-dose combination therapy in hypertension. Am Fam Physician. 1997;56:1275–1279
  8. Rosenthal T, Gavras I. Fixed-dose combinations as first-line treatment for hypertension. Prog Cardiovasc Dis. 2006;48:416–425
  9. Fretheim A, Oxman AD. International variation in prescribing antihypertensive drugs: its extent and possible explanations. BMC Health Serv Res. 2005;5:21
  10. Bateman DN, Dean CR, Mucklow JC, et al. Atenolol and chlorthalidone in combination for hypertension. Br J Clin Pharmacol. 1979;7:357–363
  11. Chalmers JP, Korner PI, Tiller DJ, et al. Double-blind factorial trial of prindolol and hydrochlorothiazide in hypertension. Med J Aust. 1976;1:650–653
  12. Chalmers J, Horvath J, Tiller D, Bune A. Effects of timolol and hydrochlorothiazide on blood-pressure and plasma renin activity. Lancet. 1976;2:328–331
  13. Chalmers JP, Wing LMH, Grygiel JJ, et al. Effects of once daily indapamide and pindolol on blood pressure, plasma aldosterone concentration and plasma renin activity in a general practice setting. Eur J Clin Pharmacol. 1982;22:191–196
  14. Chrysant SG, Chappel C, Farnham J, et al. Antihypertensive and metabolic effects of single and combined atenolol regimens. J Clin Pharmacol. 1992;32:61–65
  15. Durel LA, Hayashi PJ, Weidler DJ, Schneiderman N. Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination. J Clin Pharmacol. 1992;32:564–570
  16. Erwteman TM, Nagelkerke N, Lubsen J, et al. b Blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial. BMJ. 1984;289:406–409
  17. Frishman WH, Burris JF, Mroczek WJ, et al. First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension. J Clin Pharmacol. 1995;35:182–188
  18. Lacourcière Y, Arnott W. Placebo-controlled comparison of the effects of nebivolol and low-dose hydrochlorothiazide as monotherapies and in combination on blood pressure and lipid profile in hypertensive patients. J Hum Hypertens. 1994;8:283–288
  19. Zachariah PK, Messerli FH, Mroczek W. Low-dose bisoprolol/hydrochlorothiazide: an option in first-line, antihypertensive treatment. Clin Ther. 1993;15:779–787
  20. Brown CL, Backhouse CI, Grippat JC, Santoni JP. The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects. Eur J Clin Pharmacol. 1990;39:327–332
  21. Canter D, Frank GJ, Knapp LE, et al. Quinapril and hydrochlorothiazide combination for control of hypertension: assessment by factorial design. J Hum Hypertens. 1994;8:155–162
  22. Chalmers JP, Morris MJ, Wing LMH, et al. Effects of enalapril and hydrochlorothiazide on blood pressure, renin-angiotensin system, and atrial natriuretic factor in essential hypertension: a double blind factorial cross-over study. Aust NZ J Med. 1986;16:475–480
  23. Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. Arch Intern Med. 1994;154:737–743
  24. Chrysant SG, Fagan T, Glazer R, Kriegman A. Effects of benazepril and hydrochlorothiazide, given alone and in low- and high-dose combinations, on blood pressure in patients with hypertension. Arch Fam Med. 1996;5:17–24
  25. Fernández M, Madero R, González D, et al. Combined versus single effect of fosinopril and hydrochlorothiazide in hypertensive patients. Hypertension. 1994;23(Suppl I):I-207–I-210
  26. Kayanakis JG, Baulac L. Comparative study of once-daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension. Br J Clin Pharmacol. 1987;23(Suppl 1):89S–92S
  27. Pool J, Cushman WC, Saini RK, et al. Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension. Am J Hypertens. 1997;10:117–123
  28. Pordy RC. Cilazapril plus hydrochlorothiazide: improved efficacy without reduced safety in mild to moderate hypertension. Cardiology. 1994;85:311–322
  29. Scholze J, Breitstadt A, Cairns V, et al. Ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. J Hypertens. 1993;11:217–221
  30. Burris JF, Weir MR, Oparil S, et al. An assessment of diltiazem and hydrochlorothiazide in hypertension. JAMA. 1990;263:1507–1512
  31. Pool PE, Applegate WB, Woehler T, et al. A randomized, controlled trial comparing diltiazem, hydrochlorothiazide, and their combination in the therapy of essential hypertension. Pharmacotherapy. 1993;13:487–493
  32. Salvetti A, Magagna A, Innocenti P, et al. The combination of chlorthalidone with nifedipine does not exert an additive antihypertensive effect in essential hypertensives: a crossover multicenter study. J Cardiovasc Pharmacol. 1991;17:332–335
  33. Weir MR, Weber MA, Punzi HA, et al. A dose escalation trial comparing the combination of diltiazem SR and hydrochlorothiazide with the monotherapies in patients with essential hypertension. J Hum Hypertens. 1992;6:133–138
  34. Wing LMH, Arnolda LF, Harvey PJ, et al. Lacidipine, hydrochlorothiazide and their combination in systolic hypertension in the elderly. J Hypertens. 1997;15:1503–1510
  35. Wald DS, Law M, Mills S, et al. A 16-week, randomized, double-blind placebo-controlled cross-over trial to quantify the combined effect of an angiotensin-converting enzyme inhibitor and a β-blocker on blood pressure reduction. Clin Ther. 2008;30:2030–2039
  36. Wing LMH, Chalmers JP, West MJ, et al. Enalapril and atenolol in essential hypertension: attenuation of hypertensive effects in combination. Clin Exp Hypertens. 1988;10:119–133
  37. Clement DL, De Pue NY, Packet L. Effect of calcium antagonists on ambulatory blood pressure and its variations. J Cardiovasc Pharmacol. 1987;10(Suppl 10):S117–S119
  38. Dargie H, Cleland J, Findlay I, et al. Combination of verapamil and beta-blockers in systemic hypertension. Am J Cardiol. 1986;57:80D–82D
  39. Lyons D, Fowler G, Webster J, et al. An assessment of lacidipine and atenolol in mild to moderate hypertension. Br J Clin Pharmacol. 1994;37:45–51
  40. Maclean D, Mitchell ET, Lewis R, et al. Comparison of once daily atenolol, nitrendipine and their combination in mild to moderate essential hypertension. Br J Clin Pharmacol. 1990;29:455–463
  41. McInnes GT, Findlay IN, Murray G, et al. Cardiovascular responses to verapamil and propranolol in hypertensive patients. J Hypertens. 1985;3(Suppl 3):219–221
  42. Tonkin AL, Wing LMH, Russell AE, et al. Diltiazem and atenolol in essential hypertension: additivity of effects on blood pressure and cardiac conduction with combination therapy. J Hypertens. 1990;8:1015–1018
  43. Chan P, Lin C, Tomlinson B, et al. Additive effects of diltiazem and lisinopril in treatment of elderly patients with mild-to-moderate hypertension. Am J Hypertens. 1997;10:743–749
  44. Cushman WC, Cohen JD, Jones RP, et al. Comparison of the fixed combination of enalapril/diltiazem ER and their monotherapies in stage 1 to 3 essential hypertension. Am J Hypertens. 1998;11:23–30
  45. Frishman WH, Ram CVS, McMahon FG, et al. Comparison of amlodipine and benazepril monotherapy to amlodipine plus benazepril in patients with systemic hypertension: a randomized, double-blind, placebo-controlled, parallel-group study. J Clin Pharmacol. 1995;35:1060–1066
  46. Kuschnir E, Acuña E, Sevilla D, et al. Treatment of patients with essential hypertension: amlodipine 5 mg/benazepril 10 mg compared with amlodipine 5 mg, benazepril 20 mg, and placebo. Clin Ther. 1996;18:1213–1224
  47. Levine JH, Ferdinand KC, Cargo P, et al. Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension. Am J Hypertens. 1995;8:494–499
  48. Messerli F, Frishman WH, Elliott WJ. Effects of verapamil and trandolapril in the treatment of hypertension. Am J Hypertens. 1998;11:322–327
  49. Scholze J, Zilles P, Compagnone D. Verapamil SR and trandolapril combination therapy in hypertension—a clinical trial of factorial design. Br J Clin Pharmacol. 1998;45:491–495
  50. Scholze J, Bauer B, Massaro J. Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER. Clin Exp Hypertens. 1999;21:1447–1462
  51. Veratran Study Group. Effects of verapamil SR, trandolapril, and their fixed combination on 24-h blood pressure. Am J Hypertens. 1997;10:492–499
  52. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and strokes: a new preventive strategy. Health Technol Assess. 2003;7:31
  53. Kochar M, Guthrie R, Triscari J, et al. Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Am J Hypertens. 1999;12:797–805
  54. Benz JR, Black HR, Graff A, et al. Valsartan and hydrochlorothiazide in patients with essential hypertension (A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy). J Hum Hypertens. 1998;12:861–866
  55. Mackay JH, Arcuri KE, Goldberg AI, et al. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. Arch Intern Med. 1996;156:278–285
  56. Chrysant SG, Melino M, Karki S, et al. The Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30:587–604
  57. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data from one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913
  58. Law M, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease. BMJ. 2009;In press
  59. Hansson L, Zanchetti A, Carruthers SG, et al. HOT Study Group Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–1762
  60. Lui L, Zhang Y, Liu G, et al. FEVER Study Group The felodipine event reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157–2172
  61. Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of Mild Hypertension Study Research Group (TOMHS) Treatment of Mild Hypertension Study. JAMA. 1998;270:713–724
  62. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes (the second Appropriate Blood Pressure Control in Diabetes (ABCD) trial). Kidney Int. 2002;61:1086–1097
  63. Asselbergs FW, Diercks GFH, Hillege HL, et al. Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVENDIT) Investigators Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110:2809–2816

 Funding: None.

 Conflict of Interest: Nicholas J. Wald and Malcolm Law hold patents (EU1272220 and GB2361186) for a combination pill for the prevention of cardiovascular disease (Polypill) and together with David Wald have interests in its development.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(08)00992-3

doi:10.1016/j.amjmed.2008.09.038

The American Journal of Medicine
Volume 122, Issue 3 , Pages 290-300, March 2009

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