METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.
FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.
INTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.
FUNDING: Merck Sharp & Dohme.
METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing.
FINDINGS: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group.
INTERPRETATION: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.
FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
METHODS: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.
FINDINGS: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.
INTERPRETATION: Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.
FUNDING: National Institute of Mental Health.
HEALTH IMPACT OF DRUG POLICY BASED ON ENFORCEMENT OF PROHIBITION: The pursuit of drug prohibition has generated a parallel economy run by criminal networks. Both these networks, which resort to violence to protect their markets, and the police and sometimes military or paramilitary forces that pursue them contribute to violence and insecurity in communities affected by drug transit and sales. In Mexico, the dramatic increase in homicides since the government decided to use military forces against drug traffickers in 2006 has been so great that it reduced life expectancy in the country. Injection of drugs with contaminated equipment is a well-known route of HIV exposure and viral hepatitis transmission. People who inject drugs (PWID) are also at high risk of tuberculosis. The continued spread of unsafe injection-linked HIV contrasts the progress that has been seen in reducing sexual and vertical transmission of HIV in the last three decades. The Commission found that that repressive drug policing greatly contributes to the risk of HIV linked to injection. Policing may be a direct barrier to services such as needle and syringe programmes (NSP) and use of non-injected opioids to treat dependence among those who inject opioids, known as opioid substitution therapy (OST). Police seeking to boost arrest totals have been found to target facilities that provide these services to find, harass, and detain large numbers of people who use drugs. Drug paraphernalia laws that prohibit possession of injecting equipment lead PWID to fear carrying syringes and force them to share equipment or dispose of it unsafely. Policing practices undertaken in the name of the public good have demonstrably worsened public health outcomes. Amongst the most significant impacts of pursuit of drug prohibition identified by the Commission with respect to infectious disease is the excessive use of incarceration as a drug-control measure. Many national laws impose lengthy custodial sentences for minor, non-violent drug offenses; people who use drugs (PWUD) are over-represented in prison and pretrial detention. Drug use and drug injection occur in prisons, though their occurrence is often denied by officials. HIV and hepatitis C virus (HCV) transmission occurs among prisoners and detainees, often complicated by co-infection with TB and in many places multidrug-resistant TB, and too few states offer prevention or treatment services in spite of international guidelines that urge comprehensive measures, including provision of injection equipment, for people in state custody. Mathematical modelling undertaken by the Commission illustrates that incarceration and high HCV risk in the post-incarceration period can contribute importantly to national HCV incidence amongst PWID in a range of countries with varying levels of incarceration, different average prison sentences, durations of injection, and OST coverage levels in prison and following release. For example, in Thailand where PWID may spend nearly half their injection careers in prison, an estimated 63% of incident HCV infection could occur in prison. In Scotland, where prison sentences are shorter for PWUD and OST coverage is relatively high in prison, an estimated 54% of incident HCV infection occurs in prison, but as much as 21% may occur in the high-risk post-release period. These results underscore the importance of alternatives to prison for minor drug offences, ensuring access to OST in prison, and a seamless link from prison services to OST in the community. The evidence also clearly demonstrates that drug law enforcement has been applied in a discriminatory way against racial and ethnic minorities in a number of countries. The US is perhaps the best documented but not the only case of racial biases in policing, arrest, and sentencing. In 2014, African American men were more than five times more likely than whites to be incarcerated in their lifetime, though there is no significant difference in rates of drug use among these populations. The impact of this bias on communities of people of color is inter-generational and socially and economically devastating. The Commission also found significant gender biases in current drug policies. Of women in prison and pretrial detention around the world, a higher percentage are detained because of drug infractions than is the case for men. Women involved in drug markets are often on the bottom rungs – as couriers or drivers – and may not have information about major traffickers to trade as leverage with prosecutors. Gender and racial biases have marked overlap, making this an intersectional threat to women of color, their children, families, and communities. In both prison and the community, HIV, HCV and TB programmes for PWUD – including testing, prevention and treatment – are gravely underfunded at the cost of preventable death and disease. In a number of middle-income countries where large numbers of PWUD live, HIV and TB programmes for PWUD that were expanded with support from the Global Fund to Fight AIDS, TB and Malaria have lost funding due to changes in the Fund’s eligibility criteria. There is an unfortunate failure to emulate the example of Western European countries that have eliminated unsafe injection-linked HIV as a public health problem by sustainably scaling up prevention and care and enabling minor offenders to avert prison. Political resistance to harm reduction measures dismisses strong evidence of their effectiveness and cost-effectiveness. Mathematical modeling shows that if OST, NSP and antiretroviral therapy for HIV are all available, even if the coverage of each of them is not over 50%, their synergy can lead to effective prevention in a foreseeable future. PWUD are often not seen to be worthy of costly treatments, or they are thought not to be able to adhere to treatment regimens in spite of evidence to the contrary. Lethal drug overdose is an important public health problem, particularly in light of rising consumption of heroin and prescription opioids in some parts of the world. Yet the Commission found that the pursuit of drug prohibition can contribute to overdose risks in numerous ways. It creates unregulated illegal markets in which it is impossible to control adulterants of street drugs that add to overdose risk. Several studies also link aggressive policing to rushed injection and overdose risk. People with a history of drug use, over-represented in prison because of prohibitionist policies, are at extremely high risk of overdose when released from state custody. Lack of ready access to OST also contributes to injection of opioids, and bans on supervised injection sites cut off an intervention that has proven very effective in reducing overdose deaths. Restrictive drug policies also contribute to unnecessary controls on naloxone, a medicine that can reverse overdose very effectively. Though a small percentage of PWUD will ever need treatment for drug dependence, that minority faces enormous barriers to humane and affordable treatment in many countries. There are often no national standards for quality of drug dependence treatment and no regular monitoring of practices. In too many countries, beatings, forced labor, and denial of health care and adequate sanitation are offered in the name of treatment, including in compulsory detention centres that are more like prisons than treatment facilities. Where there are humane treatment options, it is often the case that those most in need of it cannot afford it. In many countries, there is no treatment designed particularly for women, though it is known that women’s motivations for and physiological reactions to drug use differ from those of men. The pursuit of the elimination of drugs has led to aggressive and harmful practices targeting people who grow crops used in the manufacture of drugs, especially coca leaf, opium poppy, and cannabis. Aerial spraying of coca fields in the Andes with the defoliant glyphosate (N-(phosphonomethyl glycine) has been associated with respiratory and dermatological disorders and with miscarriages. Forced displacement of poor rural families who have no secure land tenure exacerbates their poverty and food insecurity and in some cases forces them to move their cultivation to more marginal land. Geographic isolation makes it difficult for state authorities to reach drug crop cultivators in public health and education campaigns and it cuts cultivators off from basic health services. Alternative development programmes meant to offer other livelihood opportunities have poor records and have rarely been conceived, implemented, or evaluated with respect to their impact on people’s health. Research on drugs and drug policy has suffered from the lack of a diversified funding base and assumptions about drug use and drug pathologies on the part of the dominant funder, the US government. At a time when drug policy discussions are opening up around the world, there is an urgent to bring the best of non-ideologically-driven health science, social science and policy analysis to the study of drugs and the potential for policy reform.
POLICY ALTERNATIVES IN REAL LIFE: Concrete experiences from many countries that have modified or rejected prohibitionist approaches in their response to drugs can inform discussions of drug policy reform. A number of countries, such as Portugal and the Czech Republic, decriminalised minor drug offenses years ago, with significant savings of money, less incarceration, significant public health benefits, and no significant increase in drug use. Decriminalisation of minor offenses along with scaling up low-threshold HIV prevention services enabled Portugal to control an explosive unsafe injection-linked HIV epidemic and likely enabled the Czech Republic to prevent one from happening. Where formal decriminalisation may not be an immediate possibility, scaling up health services for PWUD can demonstrate the value to society of responding with support rather than punishment to people who commit minor drug infractions. A pioneering OST program in Tanzania is encouraging communities and officials to consider non-criminal responses to heroin injection. In Switzerland and the city of Vancouver, Canada, dramatic improvements in access to comprehensive harm reduction services, including supervised injection sites and heroin-assisted treatment, transformed the health picture for PWUD. Vancouver’s experience also illustrates the importance of meaningful participation of PWUD in decision-making on policies and programmes affecting their communities.
CONCLUSIONS AND RECOMMENDATIONS: Policies meant to prohibit or greatly suppress drugs present a paradox. They are portrayed and defended vigorously by many policy-makers as necessary to preserve public health and safety, and yet the evidence suggests they have contributed directly and indirectly to lethal violence, communicable disease transmission, discrimination, forced displacement, unnecessary physical pain, and the undermining of people’s right to health. Some would argue that the threat of drugs to society may justify some level of abrogation of human rights for protection of collective security, as is also foreseen by human rights law in case of emergencies. International human rights standards dictate that in such cases, societies still must choose the least harmful way to address the emergency and that emergency measures must be proportionate and designed specifically to meet transparently defined and realistic goals. The pursuit of drug prohibition meets none of these criteria. Standard public health and scientific approaches that should be part of policy-making on drugs have been rejected in the pursuit of prohibition. The idea of reducing the harm of many kinds of human behavior is central to public policy in the areas of traffic safety, tobacco and alcohol regulation, food safety, safety in sports and recreation, and many other areas of human life where the behavior in question is not prohibited. But explicitly seeking to reduce drug-related harms through policy and programmes and to balance prohibition with harm reduction is regularly resisted in drug control. The persistence of unsafe injection-linked HIV and HCV transmission that could be stopped with proven, cost-effective measures remains one of the great failures of the global responses to these diseases. Drug policy that is dismissive of extensive evidence of its own negative impact and of approaches that could improve health outcomes is bad for all concerned. Countries have failed to recognise and correct the health and human rights harms that pursuit of prohibition and drug suppression have caused and in so doing neglect their legal responsibilities. They readily incarcerate people for minor offenses but then neglect their duty to provide health services in custodial settings. They recognize uncontrolled illegal markets as the consequence of their policies, but they do little to protect people from toxic, adulterated drugs that are inevitable in illegal markets or the violence of organized criminals, often made worse by policing. They waste public resources on policies that do not demonstrably impede the functioning of drug markets, and they miss opportunities to invest public resources wisely in proven health services for people often too frightened to seek services. To move toward the balanced policy that UN member states have called for, we offer the following recommendations: Decriminalisation: Decriminalise minor, non-violent drug offenses – use, possession, and petty sale – and strengthen health and social-sector alternatives to criminal sanctions. Reducing violence and discrimination in policing: Reduce the violence and other harms of drug policing, including phasing out the use of military forces in drug policing, better targeting of policing on the most violent armed criminals, allowing possession of syringes, not targeting harm reduction services to boost arrest totals, and eliminating racial and ethnic discrimination in policing. Reducing harms: Ensure easy access for all who need them to harm reduction services as a part of responding to drugs, recognizing the effectiveness and cost-effectiveness of scaling up and sustaining these services. OST, NSP, supervised injection sites, and access to naloxone – brought to a scale adequate to meet demand – should all figure in health services and should include meaningful participation of PWUD in planning and implementation. Harm reduction services are crucial in prison and pretrial detention and should be scaled up in these settings. The 2016 UNGASS should do better than the UN Commission on Narcotic Drugs (CND) in naming harm reduction explicitly and endorsing its centrality to drug policy. Treatment and care for PWUD: Prioritize PWUD in treatment for HIV, HCV, TB, and ensure that services are adequate to ensure access for all who need care. Ensure availability of humane and scientifically sound treatment for drug dependence, including scaled-up OST in the community as well as in prisons, rejecting compulsory detention and abuse in the name of treatment. Access to controlled medicines: Ensure access to controlled medicines, establishing inter-sectoral national authorities to determine levels of need and giving the World Health Organization (WHO) the resources to assist the International Narcotics Control Board (INCB) in using the best science to determine the level of need for controlled medicines in all countries. Gender-responsive policies: Reduce the negative impact of drug policy and law on women and their families, especially minimizing custodial sentences for women who commit non-violent offenses and developing appropriate health and social support, including gender-appropriate treatment of drug dependence, for those who need it. Crop production: Efforts to address drug crop production must take health into account. Aerial spraying of toxic herbicides should be stopped, and alternative development programmes should be part of integrated development strategies, developed and implemented in meaningful consultation with the people affected. Improve research: There is a need for a more diverse donor base to fund the best new science on drug policy experiences in a non-ideological way that, among other things, interrogates and moves beyond the excessive pathologising of drug use. UN governance of drug control: UN governance of drug policy must be improved, including by respecting WHO’s authority to determine the dangerousness of drugs. Countries should be urged to include high-level health officials in their delegations to CND. Improved representation of health officials in national delegations to CND would, in turn, be a likely result of giving health authorities an important day-to-day role in multi-sectoral national drug policy-making bodies. Better metrics: Health, development, and human rights indicators should be included in metrics to judge success of drug policy; WHO and UNDP should help formulate them. UNDP has already suggested that indicators such as access to treatment, rate of overdose deaths, and access to social welfare programmes for people who use drugs would be useful indicators. All drug policies should also be monitored and evaluated as to their impact on racial and ethnic minorities, women, children and young people, and people living in poverty. Scientific approach to regulated markets: Move gradually toward regulated drug markets and apply the scientific method to their evaluation. While regulated legal drug markets are not politically possible in the short term in some places, the harms of criminal markets and other consequences of prohibition catalogued in this report are likely to lead more countries (and more US states) to move gradually in that direction, a direction we endorse. As those decisions are taken, we urge governments and researchers to apply the scientific method and ensure independent, multidisciplinary and rigorous evaluation of regulated markets to draw lessons and inform improvements in regulatory practices, and to continue evaluating and improving. We urge health professionals in all countries to inform themselves and join debates on drug policy at all levels. True to the stated goals of the international drug control regime, it is possible to have drug policy that contributes to the health and well-being of humankind, but not without bringing to bear the evidence of the health sciences and the voices of health professionals.
METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years.
FINDINGS: This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs.
INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care.
FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).