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1.  The Effects of Mandatory Prescribing of Thiazides for Newly Treated, Uncomplicated Hypertension: Interrupted Time-Series Analysis 
PLoS Medicine  2007;4(7):e232.
Background
The purpose of our study was to evaluate the effects of a new reimbursement rule for antihypertensive medication that made thiazides mandatory first-line drugs for newly treated, uncomplicated hypertension. The objective of the new regulation was to reduce drug expenditures.
Methods and Findings
We conducted an interrupted time-series analysis on prescribing data before and after the new reimbursement rule for antihypertensive medication was put into effect. All patients started on antihypertensive medication in 61 general practices in Norway were included in the analysis. The new rule was put forward by the Ministry of Health and was approved by parliament. Adherence to the rule was monitored only minimally, and there were no penalties for non-adherence. Our primary outcome was the proportion of thiazide prescriptions among all prescriptions made for persons started on antihypertensive medication. Secondary outcomes included the proportion of patients who, within 4 mo, reached recommended blood-pressure goals and the proportion of patients who, within 4 mo, were not started on a second antihypertensive drug. We also compared drug costs before and after the intervention. During the baseline period, 10% of patients started on antihypertensive medication were given a thiazide prescription. This proportion rose steadily during the transition period, after which it remained stable at 25%. For other outcomes, no statistically significant differences were demonstrated. Achievement of treatment goals was slightly higher (56.6% versus 58.4%) after the new rule was introduced, and the prescribing of a second drug was slightly lower (24.0% versus 21.8%). Drug costs were reduced by an estimated Norwegian kroner 4.8 million (€0.58 million, US$0.72 million) in the first year, which is equivalent to Norwegian kroner 1.06 per inhabitant (€0.13, US$0.16).
Conclusions
Prescribing of thiazides in Norway for uncomplicated hypertension more than doubled after a reimbursement rule requiring the use of thiazides as the first-choice therapy was put into effect. However, the resulting savings on drug expenditures were modest. There were no significant changes in the achievement of treatment goals or in the prescribing of a second antihypertensive drug.
Atle Fretheim and colleagues found that the prescribing of thiazides in Norway for uncomplicated hypertension more than doubled after a rule requiring their use as first-choice therapy was put into effect.
Editors' Summary
Background.
High blood pressure (hypertension) is a common medical condition, especially among elderly people. It has no obvious symptoms but can lead to heart attacks, heart failure, strokes, or kidney failure. It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of arteries (large blood vessels). Many factors affect blood pressure (which depends on the amount of blood being pumped round the body and on the size and condition of the arteries), but overweight people and individuals who eat fatty or salty food are at high risk of developing hypertension. Mild hypertension can often be corrected by making lifestyle changes, but many patients also take one or more antihypertensive agents. These include thiazide diuretics and several types of non-thiazide drugs, many of which reduce heart rate or contractility and/or dilate blood vessels.
Why Was This Study Done?
Antihypertensive agents are a major part of national drug expenditure in developed countries, where as many as one person in ten is treated for hypertension. The different classes of drugs are all effective, but their cost varies widely. Thiazides, for example, are a tenth of the price of many non-thiazide drugs. In Norway, the low use of thiazides recently led the government to impose a new reimbursement rule aimed at reducing public expenditure on antihypertensive drugs. Since March 2004, family doctors have been reimbursed for drug costs only if they prescribe thiazides as first-line therapy for uncomplicated hypertension, unless there are medical reasons for selecting other drugs. Adherence to the rule has not been monitored, and there is no penalty for non-adherence, so has this intervention changed prescribing practices? To find out, the researchers in this study analyzed Norwegian prescribing data before and after the new rule came into effect.
What Did the Researchers Do and Find?
The researchers analyzed the monthly antihypertensive drug–prescribing records of 61 practices around Oslo, Norway, between January 2003 and November 2003 (pre-intervention period), between December 2003 and February 2004 (transition period), and between March 2004 and January 2005 (post-intervention period). This type of study is called an “interrupted time series”. During the pre-intervention period, one in ten patients starting antihypertensive medication was prescribed a thiazide drug. This proportion gradually increased during the transition period before stabilizing at one in four patients throughout the post-intervention period. A slightly higher proportion of patients reached their recommended blood-pressure goal after the rule was introduced than before, and a slightly lower proportion needed to switch to a second drug class, but both these small differences may have been due to chance. Finally, the researchers estimated that the observed change in prescribing practices reduced drug costs per Norwegian by US$0.16 (€0.13) in the first year.
What Do These Findings Mean?
Past attempts to change antihypertensive-prescribing practices by trying to influence family doctors (for example, through education) have largely failed. By contrast, these findings suggest that imposing a change on them (in this case, by introducing a new reimbursement rule) can be effective (at least over the short term and in the practices included in the study), even when compliance with the change is not monitored nor noncompliance penalized. However, despite a large shift towards prescribing thiazides, three-quarters of patients were still prescribed non-thiazide drugs (possibly because of doubts about the efficacy of thiazides as first-line drugs), which emphasizes how hard it is to change doctors' prescribing habits. Further studies are needed to investigate whether the approach examined in this study can effectively contain the costs of antihypertensive drugs (and of drugs used for other common medical conditions) in the long term and in other settings. Also, because the estimated reduction in drug costs produced by the intervention was relatively modest (although likely to increase over time as more patients start on thiazides), other ways to change prescribing practices and produce savings in national drug expenditures should be investigated.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040232.
MedlinePlus encyclopedia page on hypertension (in English and Spanish)
UK National Institute for Health and Clinical Excellence information on hypertension for patients, carers, and professionals
American Heart Association information for patients on high blood pressure
An open-access research article describing the potential savings of using thiazides as the first-choice antihypertensive drug
A previous study in Norway, published in PLoS Medicine, examined what happened when doctors were actively encouraged to make more use of thiazides. There was also an economic evaluation of what this achieved
doi:10.1371/journal.pmed.0040232
PMCID: PMC1904466  PMID: 17622192
2.  New-onset diabetes and antihypertensive treatment 
Introduction
Chronic diseases substantially contribute to the continuous increase in health care expenditures, including type-2 diabetes mellitus as one of the most expensive chronic diseases.
Arterial hypertension presents a risk factor for the development of type-2 diabetes mellitus.
Numerous analyses have demonstrated that antihypertensive therapies promote the development of type-2-diabetes mellitus. Studies indicate, that the application of angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor-blockers (ARB) lead to less new-onset diabetes compared to beta-blockers, diuretics and placebo. Given that beta-blockers and diuretics impair the glucose metabolism, the metabolic effects of different antihypertensive drugs should be regarded; otherwise not only the disease itself, but also antihypertensive therapies may promote the development of new-onset diabetes. Even though, the cost of ACE inhibitors and ARB are higher, the use in patients with metabolic disorders could be cost-effective in the long-term if new-onset diabetes is avoided.
Objectives
To evaluate which class of antihypertensive agents promote the development or the manifestation of type-2 diabetes mellitus. How high is the incidence of new-onset diabetes during antihypertensive therapy and how is treatment-induced type-2 diabetes mellitus evaluated clinically? Which agents are therefore cost-effective in the long term? Which ethical, social or legal aspects should be regarded?
Methods
A systematic literature review was conducted including clinical trials with at least ten participants which reported new-onset diabetes in the course of antihypertensive treatment. The trials had to be published after 1966 (after 2003 for economic publications) in English or German.
Results
A total of 34 clinical publications meet the inclusion criteria. Of these, eight publications focus on the development of diabetes mellitus under treatment with diuretic and/or beta-blockers, six publications focused on ACE inhibitors alone or in combination with calcium-channel-blockers, ten publications on ARB and/or ACE inhibitors with respect to their effects on new-onset diabetes or their preventive aspects. Furthermore, five publications investigate the role of calcium-channel-antagonists in the development of diabetes, and five publications indicate the development of new-onset diabetes with different antihypertensive agents amongst each other or in comparison to no antihypertensive treatment. The clinical trials show a significant difference in the development of new-onset diabetes. Therapies with diuretics and/or beta-blockers result in a higher incidence of new-onset diabetes. ARB as well as ACE inhibitors have a preventive effect and calcium-channel-blockers show a neutral position regarding the development of new-onset diabetes.
Two publications report on economic results. The first one evaluates the cost-effectiveness of ARB alone or in combination with calcium-channel-blockers in comparison to diuretics alone or in combination with beta-blockers. The second publication compares economic outcomes of calcium-channel-blockers and beta-blockers considering the development of new-onset diabetes. Treatment with the ARB candesartan lead to savings in total costs of 549 US-Dollar per patient and in incremental costs of 30,000 US-Dollar per diabetes mellitus avoided. In the second publication, costs to the amount of 18,965 Euro in Great Britain and 13,210 Euro in Sweden are quoted for an avoided event. The treatment with calcium-channel-blockers compared to beta-blockers is proven to be more cost-effective.
No publications were identified regarding ethical, social and legal aspects.
Discussion
The available meta-analyses allow for a high clinical evidence level. A few studies vary in terms of diabetes definition and study duration. In most of the trials, the incidence of new-onset diabetes is not an endpoint. The evaluation of treatment-induced diabetes mellitus cannot be conducted, due to the lack of sufficient results in the identified literature. The two economic studies do not address all the objectives sufficiently. Ethical, social and legal aspects are discussed but not analysed systematically.
Conclusion
Based on these studies, sufficient evidence to confirm the presumption that diuretics and/or beta-blockers promote the development of new-onset diabetes compared to other antihypertensive agents, especially in patients who are predisposed, is presented with this report. Trials reflecting the clinical relevance of treatment-induced diabetes mellitus compared to existing diabetes mellitus regarding cardiovascular outcomes are required. Also health economic evaluations considering the development of new-onset diabetes should be conducted for the different classes of antihypertensive agents.
doi:10.3205/hta000081
PMCID: PMC3010880  PMID: 21289876
diabetes mellitus, type 2; hypertension; Angiotensin-converting enzyme inhibitors; Angiotensin II type receptor blockers; calcium channel blockers; diuretics
3.  What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment? 
Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology.
doi:10.1186/1475-2840-11-32
PMCID: PMC3351968  PMID: 22490507
Amlodipine; Angiotensin receptor II blocker; Diabetes mellitus; Hydrochlorothiazide; Hypertension; Renal impairment; Single-pill combination; Telmisartan
4.  Rational Prescribing in Primary Care (RaPP): A Cluster Randomized Trial of a Tailored Intervention 
PLoS Medicine  2006;3(6):e134.
Background
A gap exists between evidence and practice regarding the management of cardiovascular risk factors. This gap could be narrowed if systematically developed clinical practice guidelines were effectively implemented in clinical practice. We evaluated the effects of a tailored intervention to support the implementation of systematically developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease.
Methods and Findings
We conducted a cluster-randomized trial comparing a tailored intervention to passive dissemination of guidelines in 146 general practices in two geographical areas in Norway. Each practice was randomized to either the tailored intervention (70 practices; 257 physicians) or control group (69 practices; 244 physicians). Patients started on medication for hypertension or hypercholesterolemia during the study period and all patients already on treatment that consulted their physician during the trial were included. A multifaceted intervention was tailored to address identified barriers to change. Key components were an educational outreach visit with audit and feedback, and computerized reminders linked to the medical record system. Pharmacists conducted the visits. Outcomes were measured for all eligible patients seen in the participating practices during 1 y before and after the intervention. The main outcomes were the proportions of (1) first-time prescriptions for hypertension where thiazides were prescribed, (2) patients assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs, and (3) patients treated for hypertension or hypercholesterolemia for 3 mo or more who had achieved recommended treatment goals.
The intervention led to an increase in adherence to guideline recommendations on choice of antihypertensive drug. Thiazides were prescribed to 17% of patients in the intervention group versus 11% in the control group (relative risk 1.94; 95% confidence interval 1.49–2.49, adjusted for baseline differences and clustering effect). Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.
Conclusions
Our tailored intervention had a significant impact on prescribing of antihypertensive drugs, but was ineffective in improving the quality of other aspects of managing hypertension and hypercholesterolemia in primary care.
Editors' Summary
Background.
An important issue in health care is “getting research into practice,” in other words, making sure that, when evidence from research has established the best way to treat a disease, doctors actually use that approach with their patients. In reality, there is often a gap between evidence and practice.
  An example concerns the treatment of people who have high blood pressure (hypertension) and/or high cholesterol. These are common conditions, and both increase the risk of having a heart attack or a stroke. Research has shown that the risks can be lowered if patients with these conditions are given drugs that lower blood pressure (antihypertensives) and drugs that lower cholesterol. There are many types of these drugs now available. In many countries, the health authorities want family doctors (general practitioners) to make better use of these drugs. They want doctors to prescribe them to everyone who would benefit, using the type of drugs found to be most effective. When there is a choice of drugs that are equally effective, they want doctors to use the cheapest type. (In the case of antihypertensives, an older type, known as thiazides, is very effective and also very cheap, but many doctors prefer to give their patients newer, more expensive alternatives.) Health authorities have issued guidelines to doctors that address these issues. However, it is not easy to change prescribing practices, and research in several countries has shown that issuing guidelines has only limited effects.
Why Was This Study Done?
The researchers wanted—in two parts of Norway—to compare the effects on prescribing practices of what they called the “passive dissemination of guidelines” with a more active approach, where the use of the guidelines was strongly promoted and encouraged.
What Did the Researchers Do and Find?
They worked with 146 general practices. In half of them the guidelines were actively promoted. The remaining were regarded as a control group; they were given the guidelines but no special efforts were made to encourage their use. It was decided at random which practices would be in which group; this approach is called a randomized controlled trial. The methods used to actively promote use of the guidelines included personal visits to the practices by pharmacists and use of a computerized reminder system. Information was then collected on the number of patients who, when first treated for hypertension, were prescribed a thiazide. Other information collected included whether patients had been properly assessed for their level of risk (for strokes and heart attacks) before antihypertensive or cholesterol-lowering drugs were given. In addition, the researchers recorded whether the recommended targets for improvement in blood pressure and cholesterol level had been reached.
Only 11% of those patients visiting the control group of practices who should have been prescribed thiazides, according to the guidelines, actually received them. Of those seen by doctors in the practices where the guidelines were actively promoted, 17% received thiazides. According to statistical analysis, the increase achieved by active promotion is significant. Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.
What Do These Findings Mean?
Even in the active promotion group, the great majority of patients (83%) were still not receiving treatment according to the guidelines. However, active promotion of guidelines is more effective than simply issuing the guidelines by themselves. The study also demonstrates that it is very hard to change prescribing practices. The efforts made here to encourage the doctors to change were considerable, and although the results were significant, they were still disappointing. Also disappointing is the fact that achievement of treatment goals was no better in the active-promotion group. These issues are discussed further in a Perspective about this study (DOI: 10.1371/journal.pmed.0030229).
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030134.
• The Web site of the American Academy of Family Physicians has a page on heart disease
• The MedlinePlus Medical Encyclopedia's pages on heart diseases and vascular diseases
• Information from NHS Direct (UK National Health Service) about heart attack and stroke
• Another PLoS Medicine article has also addressed trends in thiazide prescribing
Passive dissemination of management guidelines for hypertension and hypercholesterolaemia was compared with active promotion. Active promotion led to significant improvement in antihypertensive prescribing but not other aspects of management.
doi:10.1371/journal.pmed.0030134
PMCID: PMC1472695  PMID: 16737346
5.  The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and treatment of hypertension in adults for 2010.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, randomized trials and systematic reviews of trials were preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the general lack of long-term morbidity and mortality data in this field. Progressive renal impairment was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane Collaboration librarian conducted an independent MEDLINE search from 2008 to August 2009 to update the 2009 recommendations. To identify additional studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to 1500 mg (65 mmol) per day in adults 50 years of age or younger, to 1300 mg (57 mmol) per day in adults 51 to 70 years of age, and to 1200 mg (52 mmol) per day in adults older than 70 years of age; perform 30 min to 60 min of moderate aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week for men or nine standard drinks per week for women; follow a diet that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, and that is low in saturated fat and cholesterol; and consider stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, considerations for initial therapy should include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. The combination of ACE inhibitors and ARBs should not be used, unless compelling indications are present to suggest consideration of dual therapy.
Agents appropriate for first-line therapy for isolated systolic hypertension include thiazide diuretics, long-acting dihydropyridine CCBs or ARBs. In patients with coronary artery disease, ACE inhibitors, ARBs or beta-blockers are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. In selected high-risk patients in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide diuretic. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian lipid treatment guidelines. Selected patients with hypertension who do not achieve thresholds for statin therapy, but who are otherwise at high risk for cardiovascular events, should nonetheless receive statin therapy. Once blood pressure is controlled, low-dose acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to the strength of the evidence and voted on by the 63 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 80% consensus. These guidelines will continue to be updated annually.
SPONSORS:
The Canadian Hypertension Education Program process is sponsored by the Canadian Hypertension Society, Blood Pressure Canada, the Public Health Agency of Canada, the College of Family Physicians of Canada, the Canadian Pharmacists Association, the Canadian Council of Cardiovascular Nurses, and the Heart and Stroke Foundation of Canada.
PMCID: PMC2886555  PMID: 20485689
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
6.  What differentiates primary care physicians who predominantly prescribe diuretics for treating mild to moderate hypertension from those who do not? A comparative qualitative study 
BMC Family Practice  2012;13:9.
Background
Thiazide diuretics are cost-effective for the treatment of mild to moderate hypertension, but physicians often opt for more expensive treatment options such as angiotensin II receptor blockers or angiotensin converting enzyme inhibitors. With escalating health care costs, there is a need to elucidate the factors influencing physicians' treatment choices for this highly prevalent chronic condition. The purpose of this study was to describe the characteristics of physicians' decision-making process regarding hypertension treatment choices.
Methods
A comparative qualitative study was conducted in 2009 in the Canadian province of Quebec. Overall, 29 primary care physicians--who are also participating in an electronic health record research program--participated in a semi-structured interview about their prescribing decisions. Physicians were categorized into two groups based on their patterns of prescribing antihypertensive drugs: physicians who predominantly prescribe diuretics, and physicians who predominantly prescribe drug classes other than diuretics. Cases of hypertension that were newly started on antihypertensive therapy were purposely selected from each physician's electronic health record database. Chart stimulated recall interview, a technique utilizing patient charts to probe recall and provide context to physician decision-making during clinical encounters, was used to elucidate reasons for treatment choices. Interview transcripts were synthesized using content analysis techniques, and factors influencing physicians' decision making were inductively generated from the data.
Results
We identified three themes that differentiated physicians who predominantly prescribe diuretics from those who predominantly prescribe other drug classes for the initial treatment of mild to moderate hypertension: a) perceptions about the efficacy of diuretics, b) preferred approach to hypertension management and, c) perceptions about hypertension guidelines. Specifically, physicians had differences in beliefs about the efficacy, safety and tolerability of diuretics, the most effective approach for managing mild to moderate hypertension, and in aggressiveness to achieve treatment targets. Marketing strategies employed by the pharmaceutical industry and practice experience appear to contribute to these differences in management approach.
Conclusions
Physicians preferring more expensive treatment options appear to have several misperceptions about the efficacy, safety and tolerability of diuretics. Efforts to increase physicians' prescribing of diuretics may need to be directed at overcoming these misperceptions.
doi:10.1186/1471-2296-13-9
PMCID: PMC3313881  PMID: 22375684
Hypertension; Antihypertensive treatments; Physician; Prescribing behavior; Cost-effectiveness; Qualitative study
7.  Primary stroke prevention and hypertension treatment: which is the first-line strategy? 
Neurology International  2011;3(2):e12.
Hypertension (HT) is considered the main classic vascular risk factor for stroke and the importance of lowering blood pressure (BP) is well established. However, not all the benefit of antihypertensive treatment is due to BP reduction per se, as the effect of reducing the risk of stroke differs among classes of antihypertensive agents. Extensive evidences support that angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide diuretics each reduced risk of stroke compared with placebo or no treatment. Therefore, when combination therapy is required, a combination of these antihypertensive classes represents a logical approach. Despite the efficacy of antihypertensive therapy a large proportion of the population, still has undiagnosed or inadequately treated HT, and remain at high risk of stroke. In primary stroke prevention current guidelines recommend a systolic/diastolic BP goal of <140/<90 mmHg in the general population and <130/80 mmHg in diabetics and in subjects with high cardiovascular risk and renal disease. The recent release in the market of the fixed-dose combination (FDC) of ACEI or ARB and CCB should provide a better control of BP. However to confirm the efficacy of the FDC in primary stroke prevention, clinical intervention trials are needed.
doi:10.4081/ni.2011.e12
PMCID: PMC3207231  PMID: 22053259
antihypertensive therapy; hypertension; prevention; renin angiotensin system; stroke.
8.  Tailoring Antihypertensive Drug Therapy for the Black Patient 
Blacks experience greater incidence, morbidity, and mortality from hypertension in comparison with whites. Blacks also respond differently to antihypertensive agents. While whites tend to respond in similar fashion to many of the different classes of antihypertensives, blacks consistently have the best response to thiazide diuretics. When a second drug is needed for blood pressure control, there are a number of choices: a beta-blocker, an alpha-beta blocker, an alphablocker, a centrally acting agent, a peripherally acting agent, an angiotensin-converting enzyme (ACE) inhibitor, or a calcium channel blocker. Choosing among these involves considerations of efficacy, likelihood of compliance, and symptomatic and metabolic side effects—all important factors. Clinical experience with the ACE inhibitors, and captopril in particular, has shown the value of adding such a drug to a diuretic regimen, both in terms of controlling blood pressure and reducing metabolic derangements, and subsequently, cardiovascular risk factors. Labetalol, the alpha-beta blocker, and prazosin, the alphablocker, have also produced good results in some studies when combined with a thiazide in black patients.
PMCID: PMC2571459  PMID: 3560241
9.  Clinical Outcomes by Race in Hypertensive Patients with and without the Metabolic Syndrome in ALLHAT 
Archives of internal medicine  2008;168(2):207-217.
Background
Antihypertensive drugs with favorable metabolic effects on glucose and lipid levels are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in black and nonblack hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an α-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril).
Methods
A post hoc subgroup analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled hypertension treatment trial in 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30 kg/m2, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men (or less than 50 mg/dL in women).
Results
Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval [CI], 1.18–1.90), 1.49 (95% CI, 1.17–1.90), and 1.88 (95% CI, 1.42–2.47) in black participants and 1.25 (95% CI, 1.06–1.47), 1.20 (95% CI, 1.01–1.41), and 1.82 (95% CI, 1.51–2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RR, 1.24 [95% CI, 1.09–1.40] and 1.10 [95% CI, 1.02–1.19], respectively) and doxazosin-chlorthalidone comparisons (RR, 1.37 [95% CI, 1.19–1.58] and 1.18 [95% CI, 1.08– 1.30], respectively), in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [95% CI, 1.07–1.76] for the lisinopril-chlorthalidone comparison; RR, 1.49 [95% CI, 1.09–2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 1 [95% CI, 1.13– 2.55]) with lisinopril compared with chlorthalidone.
Conclusions
The ALLHAT findings fail to do not support the preference of for calcium channel blockers, α-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.
doi:10.1001/archinternmed.2007.66
PMCID: PMC2805022  PMID: 18227370
10.  Blood pressure reduction, persistence and costs in the evaluation of antihypertensive drug treatment – a review 
Background
Blood pressure lowering drugs are usually evaluated in short term trials determining the absolute blood pressure reduction during trough and the duration of the antihypertensive effect after single or multiple dosing. A lack of persistence with treatment has however been shown to be linked to a worse cardiovascular prognosis. This review explores the blood pressure reduction and persistence with treatment of antihypertensive drugs and the cost consequences of poor persistence with pharmaceutical interventions in arterial hypertension.
Methods
We have searched the literature for data on blood pressure lowering effects of different antihypertensive drug classes and agents, on persistence with treatment, and on related costs. Persistence was measured as patients' medication possession rate. Results are presented in the form of a systematic review.
Results
Angiotensin II receptor blocker (ARBs) have a competitive blood pressure lowering efficacy compared with ACE-inhibitors (ACEi) and calcium channel blockers (CCBs), beta-blockers (BBs) and diuretics. 8 studies describing the persistence with treatment were identified. Patients were more persistent on ARBs than on ACEi and CCBs, BBs and diuretics. Thus the product of blood pressure lowering and persistence was higher on ARBs than on any other drug class. Although the price per tablet of more recently developed drugs (ACEi, ARBs) is higher than that of older ones (diuretics and BBs), the newer drugs result in a more favourable cost to effect ratio when direct drug costs and indirect costs are also considered.
Conclusion
To evaluate drugs for the treatment of hypertension several key variables including the blood pressure lowering effect, side effects, compliance/persistence with treatment, as well as drug costs and direct and indirect costs of medical care have to be considered. ARBs, while nominally more expensive when drug costs are considered only, provide substantial cost savings and may prevent cardiovascular morbidity and mortality based on the more complete antihypertensive coverage. This makes ARBs an attractive choice for long term treatment of hypertension.
doi:10.1186/1475-2840-8-18
PMCID: PMC2669450  PMID: 19327149
11.  Management of hypertension in the elderly patient 
Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and ‘white coat effect’. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension–hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.
PMCID: PMC2762362  PMID: 19851513
hypertension; elderly; antihypertensive treatment; patient management
12.  Spectrum of antihypertensive therapy in South Asians at a tertiary care hospital in Pakistan 
BMC Research Notes  2011;4:318.
Background
Despite available guidelines on hypertension (HTN), use of antihypertensives is variable. This study was designed to ascertain frequency of patients on monotherapy and > 1 antihypertensive therapy and also to ascertain proportion of patients on diuretic therapy.
Methods
It was a crossectional study conducted on 1191 adults(age > 18 yrs)hypertensive patients selected by computerized International Classification of Diseases -9-coordination and maintenance (ICD-9-CM) presenting to a tertiary care hospital in Pakistan. Data on demographics, comorbids, type of antihypertensive drug, number of antihypertensive drug and mean duration of antihypertensive drug was recorded over 1.5 year period (2008-09). Blood pressure was recorded on admission. Primary outcome was use of combination therapy and secondary outcome was use of diuretic therapy.
Results
A total of 1191 participants were included. Mean age(SD) was 62.55(12.47) years, 45.3%(540) were males. Diabetes was the most common comorbid; 46.3%(551). Approximately 85% of patients had controlled hypertension. On categorization of anti hypertensive use into 3 categories;41.2%(491) were on monotherapy,32.2%(384) were on 2 drug therapy,26.5%(316) were on ≥3 drug therapy. Among those who were on monotherapy for HTN;34%(167) were on calcium channel blockers,30.10%(148) were on beta blockers, 22.80%(112) were on Angiotensin converting enzyme (ACE) inhibitors,12%(59) were on diuretics and 2.20%(11) were on Angiotensin receptor blockers(ARB). Use of combination antihypertensive therapy was significantly high in patients with ischemic heart disease(IHD)(p < 0.001). Use of diuretics was in 31% (369) patients. Use of diuretics was significantly less in patients with comorbids of diabetes (p 0.02), Chronic kidney disease(CKD)(p 0.003), IHD (p 0.001) respectively
Conclusion
Most patients presenting to our tertiary care center were on combination therapy. Calcium channel blocker is the most common anti hypertensive drug used as monotherapy and betablockers are used as the most common antihypertensive in combination. Only a third of patients were on diuretic as an antihypertensive therapy.
doi:10.1186/1756-0500-4-318
PMCID: PMC3171374  PMID: 21884613
13.  Maximising antihypertensive effects of angiotensin II receptor blockers with thiazide diuretic combination therapy: focus on irbesartan/hydrochlorothiazide 
Background
Evidence-based guidelines for the management of hypertension are now well established. Studies have shown that more than 60% of patients with hypertension will require two or more drugs to achieve current treatment targets.
Discussion
Combination therapy is recommended as first-line treatment by the JNC-7 guidelines for patients with a blood pressure > 20 mmHg above the systolic goal or 10 mmHg above the diastolic goal, while the International Society of Hypertension in Blacks recommends combination therapy when BP exceeds targets by > 15/10 mmHg. Current European Society of Hypertension-European Society of Cardiology guidelines also recommend the use of low-dose combination therapy in the first-line setting. Furthermore, JNC-7 recommends that a thiazide-type diuretic should be part of initial first-line combination therapy. Thiazide/diuretic combinations are available for a variety of classes of antihypertensive, including ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers and centrally acting agents. This article focuses on clinical data investigating the combination of an ARB, irbesartan, with the diuretic, hydrochlorothiazide.
Conclusions
These data indicate that the ARB/HCTZ combination has greater potency and a similar side effect profile to ARB monotherapy and represents a highly effective approach for attaining goal BP levels using a therapeutic strategy that very effectively lowers BP, is well tolerated and minimises diuretic-induced metabolic effects.
Review CriteriaThe PubMed and other searchable databases were utilized to collate information from original and review articles as well as from selected abstracts relevant to this topic.Message for the ClinicDiuretic-based combination antihypertensive drug therapy is a cornerstone of antihypertensive drug therapy. Most hypertensive patients will require more than one antihypertensive drug to lower blood pressure (BP) below target levels. The combination of diuretics with renin angiotensin system antagonists is highly logical given the significant augmentation of BP response and the minimization of drug-specific side effects (e.g., hypo- and hyperkalemia) when these two drug classes are combined. The combined use of angiotensin receptor blockers and diuretics is better tolerated, but more costly, than generic angiotensin converting enzyme inhibitors and diuretics, mostly because of the absence of cough and much lower incidence of angioedema.
doi:10.1111/j.1742-1241.2007.01577.x
PMCID: PMC2228392  PMID: 17887997
14.  Rational Prescribing in Primary Care (RaPP): Economic Evaluation of an Intervention to Improve Professional Practice 
PLoS Medicine  2006;3(6):e216.
Background
Interventions designed to narrow the gap between research findings and clinical practice may be effective, but also costly. Economic evaluations are necessary to judge whether such interventions are worth the effort. We have evaluated the economic effects of a tailored intervention to support the implementation of guidelines for the use of antihypertensive and cholesterol-lowering drugs. The tailored intervention was evaluated in a randomized trial, and was shown to significantly increase the use of thiazides for patients started on antihypertensive medication, but had little or no impact on other outcomes. The increased use of thiazides was not expected to have an impact on health outcomes.
Methods and Findings
We performed cost-minimization and cost-effectiveness analyses on data from a randomized trial involving 146 general practices from two geographical areas in Norway. Each practice was randomized to either the tailored intervention (70 practices; 257 physicians) or control group (69 practices; 244 physicians). Only patients that were being started on antihypertensive medication were included in the analyses. A multifaceted intervention was tailored to address identified barriers to change. Key components were an educational outreach visit with audit and feedback, and computerized reminders. Pharmacists conducted the visits. A cost-minimization framework was adopted, where the costs of intervention were set against the reduced treatment costs (principally due to increased use of thiazides rather than more expensive medication). The cost-effectiveness of the intervention was estimated as the cost per additional patient being started on thiazides. The net annual cost (cost minimization) in our study population was US$53,395, corresponding to US$763 per practice. The cost per additional patient started on thiazides (cost-effectiveness) was US$454. The net annual savings in a national program was modeled to be US$761,998, or US$540 per practice after 2 y. In this scenario the savings exceeded the costs in all but two of the sensitivity analyses we conducted, and the cost-effectiveness was estimated to be US$183.
Conclusions
We found a significant shift in prescribing of antihypertensive drugs towards the use of thiazides in our trial. A major reason to promote the use of thiazides is their lower price compared to other drugs. The cost of the intervention was more than twice the savings within the time frame of our study. However, we predict modest savings over a 2-y period.
Editors' Summary
Background
The importance of bridging the gap between research and practice, and the need to improve the prescribing practices of family doctors (general practitioners), is discussed in the Editors' Summary for an article related to this one (DOI: 10.1371/journal.pmed.0030134). However, measures to improve prescribing practice can be expensive. Economic evaluations are necessary to judge whether such measures are worth the effort.
Doctors in a Norwegian study, described in the related article, were encouraged to make more use of drugs belonging to the thiazide “family” to treat high blood pressure (hypertension). Thiazides are cheaper than other antihypertensive drugs and in the average patient at least as effective. Increasing their use should therefore save health services money, but not reduce the effectiveness of the treatment of hypertension. The study found that measures to actively encourage doctors to follow prescribing guidelines did increase the use of thiazides, but only by a small amount.
Why Was This Study Done?
After having found that active promotion of guidelines can make a difference, the researchers wanted to know whether the cost of the efforts they made to encourage doctors to follow the guidelines were justified by the savings made by increased use of the cheaper drugs.
What Did the Researchers Do and Find?
They calculated the money saved where the prescribing guidelines were actively promoted, and then worked out what this would amount to if the same were done in all the family practices in Norway. They found that the cost of promoting the guidelines was greater than the savings achieved during the course of their study, which lasted one year. However, their calculations show that after two years the money saved would have exceeded the costs. After that, the savings would increase every year.
What Do These Findings Mean?
As far as this particular example of prescribing practice is concerned, although active promotion of guidelines increased costs in the short term, it will soon produce savings. This will not always be the case; efforts to change prescribing practice may sometimes involve the use of more effective but costlier drugs. Improving the care of patients must always be the main aim, but encouraging doctors to follow recommended guidelines on the prescribing of drugs can sometimes reduce costs, too. These issues are discussed further in a Perspective about this study (DOI: 10.1371/journal.pmed.0030229).
A significant increase in prescribing of thiazides, in preference to more expensive antihypertensives, resulted from active promotion of guidelines. The cost of the intervention was greater than the saving during the study period. Modest savings are predicted after two years.
doi:10.1371/journal.pmed.0030216
PMCID: PMC1472698  PMID: 16737349
15.  Blood pressure control and antihypertensive pharmacotherapy patterns in a hypertensive population of Eastern Central Region of Portugal 
Background
Interventions to improve blood pressure control in hypertension have had limited success in clinical practice despite evidence of cardiovascular disease prevention in randomised controlled trials.
The objectives of this study were to evaluate blood pressure control and antihypertensive pharmacotherapy patterns in a population of Eastern Central Region of Portugal, attending a hospital outpatient clinic (ambulatory setting) for routine follow-up.
Methods
Medical data of all patients that attended at least two medical appointments of hypertension/dyslipidemia in a university hospital over a one and a half year period (from January 2008 to June 2009) were retrospectively analysed. Demographic variables, clinical data and blood pressure values of hypertensive patients included in the study, as well as prescribing metrics were examined on a descriptive basis and expressed as the mean ± SD, frequency and percentages. Student's test and Mann-Whitney rank sum test were used to compare continuous variables and χ2 test and Fisher exact probability test were used to test for differences between categorical variables.
Results
In all, 37% of hypertensive patients (n = 76) had their blood pressure controlled according to international guidelines. About 45.5% of patients with a target blood pressure <140/90 mmHg (n = 156) were controlled, whereas in patients with diabetes or chronic kidney disease (n = 49) the corresponding figure was only 10.2% (P < 0.001). Among patients initiating hypertension/dyslipidemia consultation within the study period 32.1% had stage 2 hypertension in the first appointment, but this figure decreased to 3.6% in the last consultation (P = 0.012). Thiazide-type diuretics were the most prescribed antihypertensive drugs (67%) followed by angiotensin receptor blockers (60%) and beta-blockers (43%). About 95.9% patients with comorbid diabetes were treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.
Conclusions
Clinically important blood pressure decreases can be achieved soon after hypertension medical appointment initiation. However, many hypertensive patients prescribed with antihypertensive therapy fail to achieve blood pressure control in clinical practice, this control being worse among patients with diabetes or chronic kidney disease. As pharmacotherapy patterns seem to coincide with international guidelines, further research is needed to identify the causes of poor blood pressure control.
doi:10.1186/1472-6963-10-349
PMCID: PMC3018453  PMID: 21192829
16.  Emerging drug combinations to optimize renovascular protection and blood pressure goals 
Hypertension and renal disease are closely related. In fact, there is an inverse linear relationship between renal function and prevalence of hypertension. Hypertensive patients with renal dysfunction exhibit a poor clinical profile, which markedly increases their risk for cardiovascular outcomes. This review considers the available evidence on the best therapeutic approach for optimizing renovascular protection in the hypertensive population. To effectively reduce or at least slow the establishment and progression of renal disease in the hypertensive population it is critical to reach blood pressure targets. Many studies have shown that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent or at least delay the development of microalbuminuria in patients with hypertension and type 2 diabetes, reduce the incidence of overt diabetic nephropathy, and are also beneficial in patients with nondiabetic renal disease. Therefore, renin-angiotensin system (RAS) inhibition plays a key role in the prevention of renal outcomes. As the majority of patients with hypertension will need at least two antihypertensive agents to achieve blood pressure goals, the use of RAS inhibitors is a mandatory part of antihypertensive therapy. The question of which antihypertensive agent is the best choice for combining with RAS blockers should be considered. Many studies have shown that diuretics and calcium channel blockers are the best choice. However, more studies are needed to clarify the subgroups of patients who will benefit more from a combination with a diuretic or from a combination with a calcium channel blocker. To date, RAS inhibitors recommended in this context are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Aliskiren, the first oral direct renin inhibitor available, has shown promising results.
doi:10.2147/IJNRD.S7048
PMCID: PMC3333805  PMID: 22536084
antihypertensive drugs; renin-angiotensin system; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers; combined therapy
17.  Current perspectives on treatment of hypertensive patients with chronic obstructive pulmonary disease 
Systemic hypertension and chronic obstructive pulmonary disease (COPD) frequently coexist in the same patient, especially in the elderly. Today, a wide variety of antihypertensive drugs with different mechanisms of action are available to the prescribing physician. In addition, combination drugs for hypertension are becoming increasingly popular. Certain antihypertensive drugs can affect pulmonary function. Therefore the management of such patients can present therapeutic challenges. We have examined the literature pertaining to the use of antihypertensive drugs in patients with systemic hypertension and coexisting COPD. Although data are often limited or of poor quality, we have attempted to review and then provide recommendations regarding the use of all the specific classes of antihypertensive drug therapies including combination drugs in patients with COPD. The antihypertensive agents reviewed include diuretics, aldosterone receptor blockers, beta blockers, combined alpha and beta blockers, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium channel blockers, alpha-1 blockers, centrally acting drugs, direct vasodilators, and combinations of these drugs. Of these classes, calcium channel blockers and angiotensin II antagonists appear to be the best initial choices if hypertension is the only indication for treatment. However, the limited data available on many of these drugs suggest that additional studies are needed to more precisely determine the best treatment choices in this widely prevalent patient group.
doi:10.2147/IBPC.S33982
PMCID: PMC3724277  PMID: 23901294
blood pressure; hypertension; COPD; treatment; antihypertensive drugs
18.  The Effect of Tobacco Control Measures during a Period of Rising Cardiovascular Disease Risk in India: A Mathematical Model of Myocardial Infarction and Stroke 
PLoS Medicine  2013;10(7):e1001480.
In this paper from Basu and colleagues, a simulation of tobacco control and pharmacological interventions to prevent cardiovascular disease mortality in India predicted that Smokefree laws and increased tobacco taxation are likely to be the most effective measures to avert future cardiovascular deaths in India.
Please see later in the article for the Editors' Summary
Background
We simulated tobacco control and pharmacological strategies for preventing cardiovascular deaths in India, the country that is expected to experience more cardiovascular deaths than any other over the next decade.
Methods and Findings
A microsimulation model was developed to quantify the differential effects of various tobacco control measures and pharmacological therapies on myocardial infarction and stroke deaths stratified by age, gender, and urban/rural status for 2013 to 2022. The model incorporated population-representative data from India on multiple risk factors that affect myocardial infarction and stroke mortality, including hypertension, hyperlipidemia, diabetes, coronary heart disease, and cerebrovascular disease. We also included data from India on cigarette smoking, bidi smoking, chewing tobacco, and secondhand smoke. According to the model's results, smoke-free legislation and tobacco taxation would likely be the most effective strategy among a menu of tobacco control strategies (including, as well, brief cessation advice by health care providers, mass media campaigns, and an advertising ban) for reducing myocardial infarction and stroke deaths over the next decade, while cessation advice would be expected to be the least effective strategy at the population level. In combination, these tobacco control interventions could avert 25% of myocardial infarctions and strokes (95% CI: 17%–34%) if the effects of the interventions are additive. These effects are substantially larger than would be achieved through aspirin, antihypertensive, and statin therapy under most scenarios, because of limited treatment access and adherence; nevertheless, the impacts of tobacco control policies and pharmacological interventions appear to be markedly synergistic, averting up to one-third of deaths from myocardial infarction and stroke among 20- to 79-y-olds over the next 10 y. Pharmacological therapies could also be considerably more potent with further health system improvements.
Conclusions
Smoke-free laws and substantially increased tobacco taxation appear to be markedly potent population measures to avert future cardiovascular deaths in India. Despite the rise in co-morbid cardiovascular disease risk factors like hyperlipidemia and hypertension in low- and middle-income countries, tobacco control is likely to remain a highly effective strategy to reduce cardiovascular deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cardiovascular diseases (CVDs) are conditions that affect the heart and/or the circulation. In coronary heart disease, for example, narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Stroke, by contrast, is a CVD in which the blood supply to the brain is interrupted. CVD has been a major cause of illness and death in high-income countries for many years, but the burden of CVD is now rapidly rising in low- and middle-income countries. Indeed, worldwide, three-quarters of all deaths from heart disease and stroke occur in low- and middle-income countries. Smoking, high blood pressure (hypertension), high blood cholesterol (hyperlipidemia), diabetes, obesity, and physical inactivity all increase an individual's risk of developing CVD. Prevention strategies and treatments for CVD include lifestyle changes (for example, smoking cessation) and taking drugs that lower blood pressure (antihypertensive drugs) or blood cholesterol levels (statins) or thin the blood (aspirin).
Why Was This Study Done?
Because tobacco use is a key risk factor for CVD and for several other noncommunicable diseases, the World Health Organization has developed an international instrument for tobacco control called the Framework Convention on Tobacco Control (FCTC). Parties to the FCTC (currently 176 countries) agree to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes. But will tobacco control measures reduce the burden of CVD effectively in low- and middle-income countries as other risk factors for CVD are becoming more common? In this mathematical modeling study, the researchers investigated this question by simulating the effects of tobacco control measures and pharmacological strategies for preventing CVD on CVD deaths in India. Notably, many of the core FCTC provisions remain poorly implemented or unenforced in India even though it became a party to the convention in 2005. Moreover, experts predict that, over the next decade, this middle-income country will contribute more than any other nation to the global increase in CVD deaths.
What Did the Researchers Do and Find?
The researchers developed a microsimulation model (a computer model that operates at the level of individuals) to quantify the likely effects of various tobacco control measures and pharmacological therapies on deaths from myocardial infarction and stroke in India between 2013 and 2022. They incorporated population-representative data from India on risk factors that affect myocardial infarction and stroke mortality and on tobacco use and exposure to secondhand smoke into their model. They then simulated the effects of five tobacco control measures—smoke-free legislation, tobacco taxation, provision of brief cessation advice by health care providers, mass media campaigns, and advertising bans—and increased access to aspirin, antihypertensive drugs, and statins on deaths from myocardial infarction and stroke. Smoke-free legislation and tobacco taxation are likely to be the most effective strategies for reducing myocardial infarction and stroke deaths over the next decade, according to the model, and the effects of these strategies are likely to be substantially larger than those achieved by drug therapies under current health system conditions. If the effects of smoke-free legislation and tobacco taxation are additive, the model predicts that these two measures alone could avert about 9 million deaths, that is, a quarter of the expected deaths from myocardial infarction and stroke in India over the next 10 years, and that a combination of tobacco control policies and pharmacological interventions could avert up to a third of these deaths.
What Do These Findings Mean?
These findings suggest that the implementation of smoke-free laws and the introduction of increased tobacco taxes in India would yield substantial and rapid health benefits by averting future CVD deaths. The accuracy of these findings is likely to be affected by the many assumptions included in the mathematical model and by the quality of the data fed into it. Importantly, however, these finding suggest that, despite the rise in other CVD risk factors such as hypertension and hyperlipidemia, tobacco control is likely to be a highly effective strategy for the reduction of CVD deaths over the next decade in India and probably in other low- and middle-income countries. Policymakers in these countries should, therefore, work towards fuller and faster implementation of the core FCTC provisions to boost their efforts to reduce deaths from CVD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001480.
The American Heart Association provides information on all aspects of cardiovascular disease; its website includes personal stories about heart attacks and stroke
The US Centers for Disease Control and Prevention has information on heart disease and on stroke (in English and Spanish
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
MedlinePlus provides links to other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The World Health Organization provides information (in several languages) about the dangers of tobacco, about the Framework Convention on Tobacco Control, and about noncommunicable diseases; its Global Noncommunicable Disease Network (NCDnet) aims to help low- and middle- income countries reduce illness and death caused by CVD and other noncommunicable diseases
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, supported by the US National Cancer Institute and other US agencies, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001480
PMCID: PMC3706364  PMID: 23874160
19.  Diabetes: treating hypertension 
Clinical Evidence  2009;2009:0608.
Introduction
Among people with diabetes, around 40% of those aged 45 years, and more than 60% of those aged 75 years and over, will have a blood pressure greater than 140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antihypertensives in people with diabetes and hypertension? What are the effects of different blood pressure targets in people with diabetes and hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha-blockers; angiotensin II receptor antagonists; angiotensin-converting enzyme (ACE) inhibitors; beta-blockers; blood pressure targets (lower or higher); calcium-channel blockers; and diuretics.
Key Points
Among people with diabetes, around 40% of those aged 45 years, and more than 60% of those aged 75 years and over, will have a blood pressure greater than 140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
We cannot be sure how different treatments compare in people with diabetes and hypertension. However, evidence suggests that either angiotensin-converting enzyme (ACE) inhibitors or diuretics are effective first-line treatments. ACE inhibitors reduce the risks of renal disease compared with placebo, and they seem to reduce cardiovascular events compared with calcium-channel blockers. However, they can cause cough and angio-oedema. Diuretics, such as chlorthalidone, reduce cardiovascular events compared with placebo, but they may increase glucose, cholesterol, and uric acid levels.Diuretics seem as effective as ACE inhibitors at preventing cardiovascular events, and they may be more effective than calcium-channel blockers at reducing the risk of heart failure. Beta-blockers may be as effective as ACE inhibitors at reducing onset of renal disease and other diabetes-related cardiovascular and microvascular events, or diabetes-related death. However, they may cause weight gain and increase the need for glucose-lowering treatment. Calcium-channel blockers seem as effective as diuretics, more effective than beta-blockers, and less effective than ACE inhibitors at reducing cardiovascular events overall, and amlodipine may be less effective at preventing heart failure compared with chlorthalidone. Angiotensin II receptor antagonists may reduce cardiovascular mortality, and seem to be associated with a lower rate of hypokalaemia compared with beta-blockers in people with diabetes, hypertension, and LVH. We don't know whether alpha-blockers reduce cardiovascular events in people with diabetes and hypertension.
It seems likely that more intensive treatment to achieve a greater reduction in blood pressure leads to a greater reduction in cardiovascular events and overall mortality. However, it is difficult to specify a target blood pressure in people with diabetes and hypertension.
PMCID: PMC2907833  PMID: 21726474
20.  Primary prevention of CVD: treating hypertension 
Clinical Evidence  2010;2010:0214.
Introduction
Hypertension (persistent diastolic blood pressure of 90 mm Hg or greater and systolic blood pressure 140 mm Hg or greater) affects 20% of the world's adult population, and increases the risk of cardiovascular disease, end-stage renal disease, and retinopathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different antihypertensive drugs for people with hypertension? What are the effects of dietary modification for people with hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: a low-salt diet, antihypertensive drugs, calcium supplements, fish oil supplements, magnesium supplements, and potassium supplements.
Key Points
Hypertension (persistent diastolic blood pressure of 90 mm Hg or greater and systolic blood pressure 140 mm Hg or greater) affects 20% of the world's adult population, and increases the risk of cardiovascular disease, end-stage renal disease, and retinopathy. Risk factors for hypertension include age, sex, race/ethnicity, genetic predisposition, diet, physical inactivity, obesity, and psychological and social characteristics.
No antihypertensive drug has been found to be more effective than the others at reducing all-cause mortality, cardiovascular mortality, or MI. Apparent differences in outcomes with different antihypertensive drugs may be due to different levels of blood pressure reduction.Diuretics may be more effective than ACE inhibitors, calcium channel blockers, and alpha-blockers at reducing heart failure.Beta-blockers may be as effective as diuretics at reducing stroke, but calcium channel blockers may be even more effective than beta-blockers or diuretics.ACE inhibitors may be more effective than calcium channel blockers for prevention of coronary heart disease.Choice of second-line antihypertensive agent should be based on other co-morbidities and likely adverse effects as we don't know which is the most likely to reduce cardiovascular events.
We found no RCT evidence assessing whether dietary modification reduces morbidity or mortality from hypertension compared with a normal diet. Advice to reduce dietary intake of salt to below 50 mmoles daily and fish oil supplementation may reduce systolic blood pressure by approximately 1 to 5 mm Hg and reduce diastolic blood pressure by 1 to 3 mm Hg in people with hypertension.We do not know whether supplementation with potassium, magnesium, or calcium is effective in reducing blood pressure.Potassium supplementation should not be used in people with kidney failure, or in people taking drugs that can increase potassium levels.Combinations of potassium plus calcium, potassium plus magnesium, and calcium plus magnesium may be no more effective than no supplementation in reducing blood pressure.
PMCID: PMC2907625  PMID: 21733198
21.  Trends in antihypertensive drug prescriptions and physician visits in Canada between 1996 and 2006 
BACKGROUND:
In 1999, the Canadian Hypertension Education Program (CHEP) was launched to develop and implement evidence-based hypertension guidelines.
OBJECTIVES:
To determine temporal trends in antihypertensive drug prescribing and physician visits for hypertension in Canada, and correlate these trends with CHEP recommendations.
METHODS:
Longitudinal drug data (Intercontinental Medical Statistics [IMS] CompuScript database; IMS Health Canada) were used to examine prescriptions over an 11-year period (1996 to 2006) for five major cardiovascular drug classes. The IMS Canadian Disease and Therapeutic Index database was used to determine trends in physician office visits for hypertension.
RESULTS:
Prescriptions for antihypertensive agents increased significantly over the 11-year period (4054% for angiotensin receptor blockers, 127% for thiazide diuretics, 108% for angiotensin-converting enzyme inhibitors, 87% for beta-blockers and 55% for calcium channel blockers). Time series analyses demonstrated increases in the growth rate for all drug classes, with the greatest annual change in prescriptions occurring during the 1999 to 2002 time period (except in angiotensin receptor blockers). An increase in prescriptions for fixed-dose combination products occurred, which was temporally related to the change in CHEP recommendations encouraging their use in 2001. The proportion of physician office visits for hypertension increased significantly from 4.9% in 1995 to 6.8% in 2005 (P<0.001).
CONCLUSIONS:
The largest increase in antihypertensive drug prescribing occurred in the period immediately following implementation of CHEP (1999 to 2002). Although prescribing rates are still increasing, the rate of change has decreased, suggesting that the treatment market for hypertension may be becoming saturated. The impact of these changes on blood pressure control and clinical outcomes remains to be determined.
PMCID: PMC2643197  PMID: 18548150
Drug therapy; Hypertension
22.  Diabetes: treating hypertension 
Clinical Evidence  2012;2012:0608.
Introduction
Among people with diabetes, about 40% of those aged 45 years, and more than 60% of those aged 75 years or over, will have a blood pressure over 140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antihypertensives in people with diabetes and hypertension? What are the effects of different blood pressure targets in people with diabetes and hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha-blockers, angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, blood pressure targets (lower or higher), calcium-channel blockers, and diuretics.
Key Points
Among people with diabetes, about 40% of those aged 45 years, and >60% of those aged 75 years or over, will have a blood pressure >140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
We cannot be sure how different treatments compare in people with diabetes and hypertension. However, evidence suggests that either angiotensin-converting enzyme (ACE) inhibitors or diuretics are effective first-line treatments.
ACE inhibitors reduce the risks of renal disease compared with placebo, and they seem to reduce cardiovascular events compared with calcium-channel blockers. However, they can cause cough and angio-oedema.
Diuretics, such as chlortalidone, reduce cardiovascular events compared with placebo, but they may increase glucose, cholesterol, and uric acid levels. Diuretics seem as effective as ACE inhibitors at preventing cardiovascular events, and they may be more effective than calcium-channel blockers at reducing the risk of heart failure.
Beta-blockers may be as effective as ACE inhibitors at reducing onset of renal disease and other diabetes-related cardiovascular and microvascular events, or diabetes-related death. However, they may cause weight gain and increase the need for glucose-lowering treatment.
Calcium-channel blockers seem as effective as diuretics, more effective than beta-blockers, and less effective than ACE inhibitors at reducing cardiovascular events overall, and amlodipine may be less effective at preventing heart failure compared with chlortalidone.
We found conflicting evidence on long-term outcomes with angiotensin II receptor antagonists (ARBs).
We don't know whether alpha-blockers reduce cardiovascular events in people with diabetes and hypertension.
It seems likely that more intensive treatment to achieve a greater reduction in blood pressure leads to a greater reduction in cardiovascular events and overall mortality. However, it is difficult to specify a target blood pressure in people with diabetes and hypertension.
PMCID: PMC3314422  PMID: 22456232
23.  The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2707169  PMID: 19417859
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
24.  Do advertisements for antihypertensive drugs in Australia promote quality prescribing? A cross-sectional study 
BMC Public Health  2008;8:167.
Background
Antihypertensive medications are widely prescribed by doctors and heavily promoted by the pharmaceutical industry. Despite strong evidence of the effectiveness and cost-effectiveness of thiazide diuretics, trends in both promotion and prescription of antihypertensive drugs favour newer, less cost-effective agents. Observational evidence shows correlations between exposure to pharmaceutical promotion and less ideal prescribing. Our study therefore aimed to determine whether print advertisements for antihypertensive medications promote quality prescribing in hypertension.
Methods
We performed a cross-sectional study of 113 advertisements for antihypertensive drugs from 4 general practice-oriented Australian medical publications in 2004. Advertisements were evaluated using a quality checklist based on a review of hypertension management guidelines. Main outcome measures included: frequency with which antihypertensive classes were advertised, promotion of thiazide class drugs as first line agents, use of statistical claims in advertisements, mention of harms and prices in the advertisements, promotion of assessment and treatment of cardiovascular risk, promotion of lifestyle modification, and targeting of particular patient subgroups.
Results
Thiazides were the most frequently advertised drug class (48.7% of advertisements), but were largely promoted in combination preparations. The only thiazide advertised as a single agent was the most expensive, indapamide. No advertisement specifically promoted any thiazide as a better first-line drug. Statistics in the advertisements tended to be expressed in relative rather than absolute terms. Drug costs were often reported, but without cost comparisons between drugs. Adverse effects were usually reported but largely confined to the advertisements' small print. Other than mentioning drug interactions with alcohol and salt, no advertisements promoted lifestyle modification. Few advertisements (2.7%) promoted the assessment of cardiovascular risk.
Conclusion
Print advertisements for antihypertensive medications in Australia provide some, but not all, of the key messages required for guideline-concordant care. These results have implications for the regulation of drug advertising and the continuing education of doctors.
doi:10.1186/1471-2458-8-167
PMCID: PMC2409327  PMID: 18492241
25.  Impact of Two Medicaid Prior-Authorization Policies on Antihypertensive Use and Costs Among Michigan and Indiana Residents Dually Enrolled in Medicaid and Medicare: Results of a Longitudinal, Population-Based Study 
Clinical therapeutics  2010;32(4):10.1016/j.clinthera.2010.04.007.
Background
In response to rising pharmaceutical costs, many state Medicaid programs have implemented policies requiring prior authorization for high-cost medications, even for established users. However, little is known about the impact of these policies on the use of antihypertensive medicines in the United States.
Objective
The aim of this longitudinal, population-based study was to assess comprehensive prior-authorization programs for antihypertensives on drug use and costs in a vulnerable Medicaid population in Michigan and Indiana.
Methods
A prior-authorization policy for anti-hypertensives was implemented in Michigan in March 2002 and in Indiana in September 2002; Indiana also implemented an antihypertensive stepwise-therapy requirement in July 2003. Our study cohort included individuals aged ≥18 years in Michigan and Indiana who were continuously enrolled in both Medicaid and Medicare from July 2000 through September 2003. Claims data were obtained from the Centers for Medicare and Medicaid Services. We included all antihypertensive medications, including diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, β-blockers, α-blockers, and angiotensin II receptor blockers. We used interrupted time-series analysis to study policy-related changes in the total number and cost of anti-hypertensive prescriptions.
Results
Overall, 38,684 enrollees in Michigan and 29,463 in Indiana met our inclusion criteria. Slightly more than half of our cohort in both states was female (53.29% in Michigan and 56.32% in Indiana). In Michigan, 20.23% of patients were aged ≥65 years; 77.44% were white, 20.11% were black, and the remainder were Hispanic, Native American, Asian, or of other or unknown race. In Indiana, 20.07% were aged ≥65 years; 84.93% were white, 13.64% were black, and the remainder were Hispanic, Native American, Asian, or of other or unknown race. The implementation of both policies was associated with large and immediate reductions in the use of nonpreferred medications: 83.33% reduction in the use of such drugs in Michigan (−84.30 prescriptions per 1000 enrollees per month; P < 0.001) and 35.76% in Indiana (−64.45 prescriptions per 1000 enrollees per month; P < 0.001). As expected, use of preferred medications also increased substantially in both states (P < 0.001). Overall, antihypertensive therapy immediately dropped 0.16% in Michigan (P = 0.04) and 1.82% in Indiana (P = 0.02). Implementation of the policies was also associated with reductions in pharmacy reimbursement of $616,572.43 in Michigan and $868,265.97 in Indiana in the first postpolicy year.
Conclusions
Prior authorization was associated with lower use of nonpreferred antihypertensive drugs that was largely offset by increases in the use of preferred drugs. The possible clinical consequences of policy-induced drug switching for individual patients remain unknown because the present study did not include access to medical record data. Further research is needed to establish whether large-scale switches in medicines following the inception of prior-authorization policies have any long-term health effects.
doi:10.1016/j.clinthera.2010.04.007
PMCID: PMC3844690  PMID: 20435243
prior authorization; Medicaid; anti-hypertensive; drug utilization; costs

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